Compounds and compositions for treating conditions associated with nlrp activity

ABSTRACT

In one aspect, compounds of Formulae (I) and (II), or pharmaceutically acceptable salts thereof, are featured: Formulae (I) and (II), wherein the variables shown in Formulae (I) and (II) can be as defined anywhere herein.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound thatmodulates (e.g., antagonizes) NLRP1 or NLRP3 or both NLRP1 and NLRP3, ora pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that are useful, e.g., fortreating a condition, disease or disorder in which a decrease orincrease in NLRP1/3 activity (e.g., an increase, e.g., a condition,disease or disorder associated with NLRP1/3 signaling) contributes tothe pathology and/or symptoms and/or progression of the condition,disease or disorder in a subject (e.g., a human). This disclosure alsofeatures compositions as well as other methods of using and making thesame.

BACKGROUND

The NLRP3 inflammasome is a component of the inflammatory process andits aberrant activation is pathogenic in inherited disorders such as thecryopyrin associated periodic syndromes (CAPS). The inherited CAPSMuckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome(FCAS) and neonatal onset multi-system inflammatory disease (NOMID) areexamples of indications that have been reported to be associated withgain of function mutations in NLRP3.

The NLRP1 inflammasome is a component of the inflammatory process andits aberrant activation is pathogenic in inherited disorders such asgeneralized vitiligo associated with autoimmune disease (autoimmunethyroid disease, latent autoimmune diabetes in adults, rheumatoidarthritis, psoriasis, pernicious anemia, systemic lupus erythematosus,and Addison's disease).

NLRP1 and NLRP3 can form a complex and they have been implicated in thepathogenesis of a number of complex diseases, including but not limitedto metabolic disorders such as type 2 diabetes, atherosclerosis, obesityand gout, as well as diseases of the central nervous system, such asAlzheimer's disease and multiple sclerosis and Amyotrophic LateralSclerosis and Parkinson disease, lung disease, such as asthma and COPDand pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome,viral hepatitis and cirrhosis, pancreatic disease, such as acute andchronic pancreatitis, kidney disease, such as acute and chronic kidneyinjury, intestinal disease such as Crohn's disease and UlcerativeColitis, skin disease such as psoriasis, musculoskeletal disease such asscleroderma, vessel disorders, such as giant cell arteritis, disordersof the bones, such as osteoarthritis, osteoporosis and osteopetrosisdisorders, eye disease, such as glaucoma and macular degeneration,diseases caused by viral infection such as HIV and AIDS, autoimmunediseases such as rheumatoid arthritis, systemic Lupus erythematosus,autoimmune thyroiditis; Addison's disease, and pernicious anemia, cancerand aging.

In light of the above, it would be desirable to provide compounds thatmodulate (e.g., antagonize) NRLP1/3, wherein the compounds inhibit NLRP1or NLRP3 or both NLRP3 and NLRP1.

SUMMARY

This disclosure features chemical entities (e.g., a compound thatmodulates (e.g., antagonizes) NLRP1 or NLRP3 or both NLRP1 and NLRP3, ora pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that are useful, e.g., fortreating a condition, disease or disorder in which a decrease orincrease in NLRP1 or NLRP3 or both NLRP1 and NLRP3 activity, alsoreferred to herein “NLRP1/3” activity (e.g., an increase, e.g., acondition, disease or disorder associated with NLRP1/3 signaling).

This disclosure also features compositions as well as other methods ofusing and making the same.

An “antagonist” of NLRP1/3 includes compounds that inhibit the abilityof NLRP1/3 to induce the production of IL-1(3 and/or IL-18 by directlybinding to NLRP1/3, or by inactivating, destabilizing, alteringdistribution, of NLRP1/3 or otherwise.

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof, are featured:

or a pharmaceutically acceptable salt thereof, wherein the variablesshown in Formula I can be as defined anywhere herein.

In one aspect, compounds of Formula II, or a pharmaceutically acceptablesalt thereof, are featured:

or a pharmaceutically acceptable salt thereof, wherein the variablesshown in Formula II can be as defined anywhere herein.

In one aspect, pharmaceutical compositions are featured that include achemical entity described herein (e.g., a compound described genericallyor specifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same) and one or more pharmaceuticallyacceptable excipients.

In one aspect, methods for modulating (e.g., agonizing, partiallyagonizing, antagonizing) NLRP1 or NLRP3 or both NLRP1 and NLRP3 activityare featured that include contacting NLRP1 or NLRP3 or both NLRP1 andNLRP3 with a chemical entity described herein (e.g., a compounddescribed generically or specifically herein or a pharmaceuticallyacceptable salt thereof or compositions containing the same). Methodsinclude in vitro methods, e.g., contacting a sample that includes one ormore cells comprising NLRP1 or NLRP3 or both NLRP1 and NLRP3 (alsoreferred to herein as “NLRP1/3”), as well as in vivo methods.

In a further aspect, methods of treatment of a disease in which NLRP1/3signaling contributes to the pathology and/or symptoms and/orprogression of the disease are featured that include administering to asubject in need of such treatment an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In a further aspect, methods of treatment are featured that includeadministering to a subject a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame), wherein the chemical entity is administered in an amounteffective to treat a disease in which NLRP1/3 signaling contributes tothe pathology and/or symptoms and/or progression of the disease, therebytreating the disease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or moreadditional therapies with one or more agents suitable for the treatmentof the condition, disease or disorder.

Examples of the indications that may be treated by the compoundsdisclosed herein include but are not limited to metabolic disorders suchas type 2 diabetes, atherosclerosis, obesity and gout, as well asdiseases of the central nervous system, such as Alzheimer' s disease andmultiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinsondisease, lung disease, such as asthma and COPD and pulmonary idiopathicfibrosis, liver disease, such as NASH syndrome, viral hepatitis andcirrhosis, pancreatic disease, such as acute and chronic pancreatitis,kidney disease, such as acute and chronic kidney injury, intestinaldisease such as Crohn' s disease and Ulcerative Colitis, skin diseasesuch as psoriasis, musculoskeletal disease such as scleroderma, vesseldisorders, such as giant cell arteritis, disorders of the bones, such asosteoarthritis, osteoporosis and osteopetrosis disorders, eye disease,such as glaucoma and macular degeneration, diseases caused by viralinfection such as HIV and AIDS, autoimmune diseases such as rheumatoidarthritis, systemic Lupus erythematosus, autoimmune thyroiditis;Addison's disease, and pernicious anemia, cancer and aging.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Descriptionand/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a numberof additional terms are defined below. Generally, the nomenclature usedherein and the laboratory procedures in organic chemistry, medicinalchemistry, and pharmacology described herein are those well-known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. Each of the patents, applications, publishedapplications, and other publications that are mentioned throughout thespecification, each of the applications from which this applicationclaims priority, and the any attached appendices, are incorporatedherein by reference in their entireties. In case of conflict between thepresent specification and any subject matter incorporated by referenceherein, the present specification, including definitions, will control.

As used herein, the term “NLRP1/3” is meant to include, withoutlimitation, nucleic acids, polynucleotides, oligonucleotides, sense andantisense polynucleotide strands, complementary sequences, peptides,polypeptides, proteins, homologous and/or orthologous NLRP molecules,isoforms, precursors, mutants, variants, derivatives, splice variants,alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound exhibiting activity as a modulator of NLRP1/3 or apharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof) being administered which will relieve to some extent one ormore of the symptoms of the disease or condition being treated. Theresult includes reduction and/or alleviation of the signs, symptoms, orcauses of a disease, or any other desired alteration of a biologicalsystem. For example, an “effective amount” for therapeutic uses is theamount of the composition comprising a compound as disclosed hereinrequired to provide a clinically significant decrease in diseasesymptoms. An appropriate “effective” amount in any individual case isdetermined using any suitable technique, such as a dose escalationstudy.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 21st ed.;Lippincott Williams & Wilkins: Philade/lphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; ThePharmaceutical Press and the American Pharmaceutical Association: 2009;Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” may refer topharmaceutically acceptable addition salts prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. In certain instances, pharmaceutically acceptable saltsare obtained by reacting a compound described herein, with acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. The term“pharmaceutically acceptable salt” may also refer to pharmaceuticallyacceptable addition salts prepared by reacting a compound having anacidic group with a base to form a salt such as an ammonium salt, analkali metal salt, such as a sodium or a potassium salt, an alkalineearth metal salt, such as a calcium or a magnesium salt, a salt oforganic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, and salts with amino acids such asarginine, lysine, and the like, or by other methods previouslydetermined. The pharmacologically acceptable salt s not specificallylimited as far as it can be used in medicaments. Examples of a salt thatthe compounds described hereinform with a base include the following:salts thereof with inorganic bases such as sodium, potassium, magnesium,calcium, and aluminum; salts thereof with organic bases such asmethylamine, ethylamine and ethanolamine; salts thereof with basic aminoacids such as lysine and ornithine; and ammonium salt. The salts may beacid addition salts, which are specifically exemplified by acid additionsalts with the following: mineral acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid:organic acids such as formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, and ethanesulfonic acid; acidic amino acids suchas aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism. Multiple techniques of administering a compoundexist in the art including, but not limited to: rectal, oral,intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topicaladministration.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease or disorder, are meant to include alleviating orabrogating a disorder, disease, or condition, or one or more of thesymptoms associated with the disorder, disease, or condition; or toslowing the progression, spread or worsening of a disease, disorder orcondition or of one or more symptoms thereof.

The terms “hydrogen” and “H” are used interchangeably herein.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, Ci-io indicates that the group may have from 1 to 10(inclusive) carbon atoms in it. Non-limiting examples include methyl,ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “carbocyclic ring” as used herein includes an aromatic ornonaromatic cyclic hydrocarbon group having 3 to 10 carbons, such as 3to 8 carbons, such as 3 to 7 carbons, which may be optionallysubstituted. Examples of carbocyclic rings include five-membered,six-membered, and seven-membered carbocyclic rings.

The term “heterocyclic ring” refers to an aromatic or nonaromatic 5-8membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclicring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms ofN, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein0, 1, 2 or 3 atoms of each ring may be substituted by a substituent.Examples of heterocyclic rings include five-membered, six-membered, andseven-membered heterocyclic rings.

The term “cycloalkyl” as used herein includes a nonaromatic cyclichydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, suchas 3 to 7 carbons, wherein the cycloalkyl group which may be optionallysubstituted. Examples of cycloalkyls include five-membered,six-membered, and seven-membered rings. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cyclooctyl.

The term “heterocycloalkyl” refers to an aromatic or nonaromatic 5-8membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclicring system radical having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6,or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,respectively), wherein 0, 1, 2 or 3 atoms of each ring may besubstituted by a substituent. Examples of heterocycloalkyls includefive-membered, six-membered, and seven-membered heterocyclic rings.Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl,tetrahydrofuranyl, and the like.

The term “hydroxy” refers to an OH group.

The term “amino” refers to an NH₂ group.

The term “oxo” refers to O. By way of example, substitution of a CH₂ agroup with oxo gives a C═O group.

As used herein, a curved line connecting two atoms indicates a chain oflength as specified by the recited number or number range. For example,a chain connecting an atom “Atom 1” to an atomo “Atom 2” may be depictedas

where the number outside the parenthetical indicates the number or rangeof numbers in the chain.

In addition, atoms making up the compounds of the present embodimentsare intended to include all isotopic forms of such atoms. Isotopes, asused herein, include those atoms having the same atomic number butdifferent mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include ¹³C and ¹⁴C.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features andadvantages of the invention will be apparent from the description anddrawings, and from the claims.

DETAILED DESCRIPTION

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C6 haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

-   and ring B is

-   wherein-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   or two R¹⁰ taken together with the carbon connecting them form a    three-to-eight-membered heterocyclic ring containing 1 or 2    heteroatoms independently selected from O, N, and S, or a    three-membered, six-membered, seven-membered, or eight-membered    carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring    is optionally substituted with one or more substituents each    independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR¹¹R¹²,    oxo, and ═NR¹³;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl;-   each R¹⁶ is the same or different and is selected from H, C₁-C₆    alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

-   or a pharmaceutically acceptable salt thereof, wherein:-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

-   wherein-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)2OH,) C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl;-   each R¹⁶ is the same or different and is selected from H, C₁-C₆    alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

-   or a pharmaceutically acceptable salt thereof, wherein:-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH,) C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl,-   CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl; each R¹⁶ is the same or different and    is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and    ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH), C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl; each R¹⁶ is the same or different and    is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²; oxo, and    ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and le are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula II

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   Y′ is N or CR^(8′);-   Z is N or CH;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, C₁-C₆ haloalkoxy, and C₁-C₆    haloalkyl;-   R^(8′) is selected from H, CN, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R^(8″) is selected from CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R^(8′″) is selected from H, CN, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,    CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆    alkyl optionally substituted with hydroxy;-   R^(3′) is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or    C₁-C₆ alkyl optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆    alkyl optionally substituted with hydroxy;-   R^(5′) is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or    C₁-C₆ alkyl optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³, if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring A,-   or R⁴ and R⁵, if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring B,-   or R² and R³, if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring A and R⁴    and R⁵, if both present, taken together with the carbons connecting    them form a four-membered to seven-membered ring B,-   R^(2″) and R^(3″), if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring A and    R^(4″) and R^(5″), if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from CN, Cl, C(R¹⁰)₂OH, or F;-   R^(1′) is selected from C(O)C₁-C₆ alkyl or CO₂C₁-C₆ alkyl;-   R^(1″) is selected from H or C(R¹⁰)₂OH;-   R¹⁴ is selected from H, CN, Cl, or F;-   R^(14′) is selected from CN or F;-   R^(14″) is selected from CN, Cl, or F;-   R⁹ is selected from H, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆    cycloalkyl, pyridyl, and morpholinyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   R^(9′) is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹²,    C₃-C₆ cycloalkyl, phenyl, pyridyl, and morpholinyl-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   or two R¹⁰ taken together with the carbon connecting them form a    three-to-eight-membered heterocyclic ring containing 1 or 2    heteroatoms independently selected from O, N, and S, or a    three-membered, six-membered, seven-membered, or eight-membered    carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring    is optionally substituted with one or more substituents each    independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²,    oxo, and ═NR¹³;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl;-   each R¹⁶ is the same or different and is selected from H, C₁-C₆    alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³.

In some embodiments, provided herein is a compound of Formula II

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH;-   Y is CR⁸;-   Y′ is CR^(8′);-   Z is N or CH;-   R⁸ is selected from H, CN, Cl, F, and CONR¹¹R¹²;-   R^(8′) is H;-   R^(8′) is selected from CN or F;-   R^(8!″) is selected from H, CN, CO₂C₁-C₆ alkyl, or CONR¹¹R¹²;-   R² is C₁-C₆ alkyl;-   R³ is hydrogen or halo;-   R^(3′) is hydrogen or halo;-   R⁴ is C₁-C₆ alkyl;-   R⁵ is hydrogen;-   R^(5′) is hydrogen;-   provided that at least one of R², R³, R⁴, and R⁵ is not hydrogen,    and that R² and R⁴ are not both hydroxymethyl;-   or R² and R³, if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring A,-   or R⁴ and R⁵, if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring B,-   or R² and R³, if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring A and R⁴    and R⁵, if both present, taken together with the carbons connecting    them form a four-membered to seven-membered ring B,-   R^(2″) and R^(3″), if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring A and    R^(4″) and R^(5″), if both present, taken together with the carbons    connecting them form a four-membered to seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring;-   n1 is 3;-   m1 is 1;-   wherein ring B is a carbocyclic ring;-   n2 is 3;-   m2 is 1;-   wherein each R⁶ in each ring is the same or different and is    selected from H;-   R¹ is selected from CN, Cl, C(R¹⁰)₂OH, or F;-   R^(1″) is selected from H or C(R¹⁰)₂OH;-   R¹⁴ is selected from H or F;-   R^(14″) _(is F;)-   R^(9′) is selected from C(R¹⁰)₂OH, C₃-C₆ cycloalkyl, phenyl,    pyridyl, or morpholinyl each R¹⁰ is the same and is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl.

In some embodiments the variables shown in the formulae herein are asfollows:

The group X¹

In some embodiments, X¹ is NH.

In some embodiments, X¹ is O

In some embodiments, X¹ and R² taken together with the atoms connectingthem form a four-to-seven-membered heterocyclic ring optionallysubstituted with one or more R¹⁶.

In some embodiments, X¹ and R⁴ taken together with the atoms connectingthem form a four-to-seven-membered heterocyclic ring optionallysubstituted with one or more R¹⁶.

In some embodiments, X¹ and R² taken together with the atoms connectingthem form a four-to-seven-membered ring C of the formula

wherein ql is 0, 1, 2 or 3; Al is N; A2 is O, NH, or CH_(2,) providedthat A1 and A2 are not both heteroatoms; and ring C is optionallysubstituted with 1 to 8 R¹⁶.

In some embodiments of ring C, Al is N and A2 is CH₂.

In some embodiments of ring C, R¹⁶ is H.

In some embodiments, ring C is a heterocyclic ring containing oneheteroatom selected from O, N and S.

In some embodiments, ring C is a heterocyclic ring containing twoheteroatoms each independently selected from O, N and S.

The groups Y and Y′

In some embodiments of one or more formulae herein, Y is CR⁸.

In some embodiments of one or more formulae herein, Y is N.

In some embodiments of one or more formulae herein, Y′ is CR^(8′).

In some embodiments of one or more formulae herein, Y′ is N.

The group Z

In some embodiments of one or more formulae herein, Z is N or CH.

In some embodiments of one or more formulae herein, Z is N.

In some embodiments of one or more formulae herein, Z is CH.

The groups R², R⁴, R³ and R⁵

In some embodiments of one or more formulae herein, R² is hydrogen.

In some embodiments of one or more formulae herein, R² is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R² is methoxy.

In some embodiments of one or more formulae herein, R² is halo.

In some embodiments of one or more formulae herein, R² is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R² is CF₃.

In some embodiments of one or more formulae herein, R² is C₁-C₆ alkyloptionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R² is isopropyl.

In some embodiments of one or more formulae herein, R² is methyl.

In some embodiments of one or more formulae herein, R³ is hydrogen.

In some embodiments of one or more formulae herein, R³ is CN.

In some embodiments of one or more formulae herein, R³ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R³ is methoxy.

In some embodiments of one or more formulae herein, R³ is halo.

In some embodiments of one or more formulae herein, R³ is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R³ is CF₃.

In some embodiments of one or more formulae herein, R³ is C₁-C₆ alkyloptionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R³ is isopropyl.

In some embodiments of one or more formulae herein, R³ is methyl.

In some embodiments of one or more formulae herein, R⁴ is hydrogen.

In some embodiments of one or more formulae herein, R⁴ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R⁴ is methoxy.

In some embodiments of one or more formulae herein, R⁴ is halo.

In some embodiments of one or more formulae herein, R⁴ is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R⁴ is CF₃.

In some embodiments of one or more formulae herein, R⁴ is C₁-C₆ alkyloptionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R⁴ is isopropyl.

In some embodiments of one or more formulae herein, R⁴ is methyl.

In some embodiments of one or more formulae herein, R⁵ is hydrogen.

In some embodiments of one or more formulae herein, R⁵ is CN.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R⁵ is methoxy.

In some embodiments of one or more formulae herein, R⁵ is halo.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R⁵ is CF₃.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆ alkyloptionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R⁵ is isopropyl.

In some embodiments of one or more formulae herein, R⁵ is methyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen.

In some embodiments of one or more formulae herein, each of R² and R⁴ isC₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R² and R⁴ isisopropyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ist-butyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ismethyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydroxymethyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ishydrogen.

In some embodiments of one or more formulae herein, each of R³ and R⁵ isC₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R³ and R⁵ isisopropyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ist-butyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ismethyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ishydroxymethyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ishydrogen and each of R² and R⁴ is C₁-C₆ alkyl optionally substitutedwith hydroxy.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ishydrogen and each of R² and R⁴ is isopropyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ishydrogen and each of R² and R⁴ is t-butyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ishydrogen and each of R² and R⁴ is methyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ ishydrogen and each of R² and R⁴ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R³ and R⁵ is C₁-C₆ alkyl optionally substitutedwith hydroxy.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R³ and R⁵ is isopropyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R³ and R⁵ is t-butyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R³ and R⁵ is methyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R³ and R⁵ is hydroxymethyl.

In some embodiments of one or more formulae herein, R² and R³ takentogether with the carbons connecting them form ring A.

In some embodiments of one or more formulae herein, R⁴ and R⁵ takentogether with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R² and R³ takentogether with the carbons connecting them form ring A and R⁴ and R⁵taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R² and R³, takentogether with the carbons connecting them form a five membered ring Aand R⁴ and R⁵, taken together with the carbons connecting them form afive-membered ring B, wherein ring A is a saturated carbocyclic ring,ring B is a saturated carbocyclic ring, n1 is 3, n2 is 3, and R⁶ is H.

The groups R^(3′) and R^(5′)

In some embodiments of one or more formulae herein, R^(3′) is hydrogen.

In some embodiments of one or more formulae herein, R^(3′) is CN.

In some embodiments of one or more formulae herein, R^(3′) is C₁-C₆alkoxy.

In some embodiments of one or more formulae herein, R^(3′) is methoxy.

In some embodiments of one or more formulae herein, R^(3′) is halo.

In some embodiments of one or more formulae herein, R^(3′) is F.

In some embodiments of one or more formulae herein, R^(3′) is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R^(3′) is CF₃.

In some embodiments of one or more formulae herein, R^(3′) is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^(3′) is isopropyl.

In some embodiments of one or more formulae herein, R^(3′) is methyl.

In some embodiments of one or more formulae herein, R^(5′) is hydrogen.

In some embodiments of one or more formulae herein, R^(5′) is CN.

In some embodiments of one or more formulae herein, R^(5′) is C₁-C₆alkoxy.

In some embodiments of one or more formulae herein, R^(5′) is methoxy.

In some embodiments of one or more formulae herein, R^(5′) is halo.

In some embodiments of one or more formulae herein, R^(5′) is F.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R^(5′) is CF₃.

In some embodiments of one or more formulae herein, R^(5′) is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^(5′) is isopropyl.

In some embodiments of one or more formulae herein, R^(5′) is methyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is hydrogen.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is isopropyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is t-butyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is methyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is hydrogen and each of R² and R⁴ is C₁-C₆ alkyl optionallysubstituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is hydrogen and each of R² and R⁴ is isopropyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is hydrogen and each of R² and R⁴ is t-butyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is hydrogen and each of R² and R⁴ is methyl.

In some embodiments of one or more formulae herein, each of R^(3′) andR^(5′) is hydrogen and each of R² and R⁴ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R^(3′) and R^(5′) is C₁-C₆ alkyl optionallysubstituted with hydroxy.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R^(3′) and R^(5′) is isopropyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R^(3′) and R^(5′) is t-butyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R^(3′) and R^(5′) is methyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ ishydrogen and each of R^(3′) and R^(5′) is hydroxymethyl.

The groups R^(2″), R^(4″), R^(3″) and R^(5″)

In some embodiments of one or more formulae herein, R^(2″) and R^(3″)taken together with the carbons connecting them form ring A and R^(4″)and R^(5″) taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R^(2″) and R3″,taken together with the carbons connecting them form a five memberedring A and R^(4″) and R^(5″), taken together with the carbons connectingthem form a five-membered ring B wherein ring A is a saturatedcarbocyclic ring and ring B is a saturated carbocyclic ring, and whereinn1 is 3, n2 is 3, and R⁶ is H.

Rings A and B

In some embodiments of one or more formulae herein, ring A is acarbocyclic ring.

In some embodiments of one or more formulae herein, ring A is aheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S.

In some embodiments of one or more formulae herein, ring B is acarbocyclic ring.

In some embodiments of one or more formulae herein, ring B is aheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S.

In some embodiments, ring A is a carbocyclic ring and n1 is 3.

In some embodiments, ring A is a carbocyclic ring and n1 is 4.

In some embodiments, ring A is a heterocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S and n1 is 3.

In some embodiments, ring A is a heterocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S and n1 is 4.

In some embodiments, ring B is a carbocyclic ring and n2 is 3.

In some embodiments, ring B is a carbocyclic ring and n2 is 4.

In some embodiments, ring B is a heterocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S and n2 is 3.

In some embodiments, ring B is a heterocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S and n2 is 4.

In some embodiments, ring A is the same as ring B.

In some embodiments, ring A is

In some embodiments, ring B is

In some embodiments, ring B is

and is the same as ring A.

In some embodiments, ring A is

In some embodiments, ring B is

and is the same as ring A.

In some embodiments, ring A is a heterocyclic ring of the formula

In some embodiments, ring A is a heterocyclic ring of the formula

The Groups R⁶ and R⁷ and the Variables n1, n2, m1 and m2 in Ring A andRing B

In some embodiments of one or more formulae herein, R⁶ is H.

In some embodiments of one or more formulae herein, R⁶ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁶ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R⁶ is methoxy.

In some embodiments of one or more formulae herein, R⁶ is NR¹¹R¹².

In some embodiments of one or more formulae herein, R⁶ is oxo.

In some embodiments of one or more formulae herein, R⁶ is ═NR¹³.

In some embodiments of one or more formulae herein, n1 is 2.

In some embodiments of one or more formulae herein, n1 is 3.

In some embodiments of one or more formulae herein, n1 is 4.

In some embodiments of one or more formulae herein, n1 is 5.

In some embodiments of one or more formulae herein, n2 is 2.

In some embodiments of one or more formulae herein, n2 is 3.

In some embodiments of one or more formulae herein, n2 is 4.

In some embodiments of one or more formulae herein, n2 is 5.

In some embodiments of one or more formulae herein, m1 is 1.

In some embodiments of one or more formulae herein, m1 is 2.

In some embodiments of one or more formulae herein, m1 is 3.

In some embodiments of one or more formulae herein, m1 is 4.

In some embodiments of one or more formulae herein, m2 is 1.

In some embodiments of one or more formulae herein, m2 is 2.

In some embodiments of one or more formulae herein, m2 is 3.

In some embodiments of one or more formulae herein, m2 is 4.

In some embodiments of one or more formulae herein, two R⁶ takentogether with the atom or atoms connecting them form a 3-to-8-memberedcarbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S.

In some embodiments of one or more formulae herein, each R⁶ in each ringis H.

In some embodiments of one or more formulae herein, each R⁶ in each ringis C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, each R⁷ in each ringis H.

In some embodiments of one or more formulae herein, each R⁷ in each ringis C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, each R⁶ in each ringis H and each R⁷ in each ring is H.

In some embodiments of one or more formulae herein, each R⁶ in each ringis H and each R⁷ in each ring is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, each R⁶ in each ringis C₁-C₆ alkyl and each R⁷ in each ring is H.

In some embodiments of one or more formulae herein, each R⁶ in each ringis C₁-C₆ alkyl and each R⁷ in each ring is C₁-C₆ alkyl.

The Ring E

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

The Groups R⁸, R^(8′), R^(8″), and R^(8′″)

In some embodiments of one or more formulae herein, R⁸ is selected fromH, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R⁸ is selected fromH, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R⁸ is H.

In some embodiments of one or more formulae herein, R⁸ is CN.

In some embodiments of one or more formulae herein, R⁸ is Cl.

In some embodiments of one or more formulae herein, R⁸ is F.

In some embodiments of one or more formulae herein, R⁸ is CO₂C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R⁸ is COCH₃.

In some embodiments of one or more formulae herein, R⁸ is CO₂C₃-C₈cycloalkyl.

In some embodiments of one or more formulae herein, R⁸ is CONH₂.

In some embodiments of one or more formulae herein, R⁸ is CONR¹¹R¹².

In some embodiments of one or more formulae herein, R⁸ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁸ is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R⁸ is CF₃.

In some embodiments of one or more formulae herein, R⁸ is haloalkoxy.

In some embodiments of one or more formulae herein, R⁸ is OCF₂.

In some embodiments of one or more formulae herein, R^(8′) is selectedfrom H, CN, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8′) is selectedfrom H, CN, F, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R^(8′) is H.

In some embodiments of one or more formulae herein, R^(8′) is CN.

In some embodiments of one or more formulae herein, R^(8′) is F.

In some embodiments of one or more formulae herein, R^(8′) is CO₂C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(8′) is COCH₃.

In some embodiments of one or more formulae herein, R^(8′) is CO₂C₃-C₈cycloalkyl.

In some embodiments of one or more formulae herein, R^(8′) is CONH₂.

In some embodiments of one or more formulae herein, R^(8′) is CONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(8′) is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(8′) is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R^(8′) is CF₃.

In some embodiments of one or more formulae herein, R^(8′) is selectedfrom CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8″) is selectedfrom CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R^(8″) is CN.

In some embodiments of one or more formulae herein, R^(8″) is Cl.

In some embodiments of one or more formulae herein, R^(8″) is F.

In some embodiments of one or more formulae herein, R^(8″) is CO₂C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(8″) is COCH₃.

In some embodiments of one or more formulae herein, R^(8″) is CO₂C₃-C₈cycloalkyl.

In some embodiments of one or more formulae herein, R^(8″) is CONH₂.

In some embodiments of one or more formulae herein, R^(8″) is CONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(8″) is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(8″) is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R^(8″) is CF₃.

In some embodiments of one or more formulae herein, R^(8″) is selectedfrom H, CN, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl,and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8′″) is selectedfrom H, CN, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R^(8′″) is H.

In some embodiments of one or more formulae herein, R^(8′″) is CN.

In some embodiments of one or more formulae herein, R^(8′″) is CO₂C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(8′″) is COCH₃.

In some embodiments of one or more formulae herein, R^(8′″) is CO₂C₃-C₈cycloalkyl.

In some embodiments of one or more formulae herein, R^(8′″) is CONH₂.

In some embodiments of one or more formulae herein, R^(8′″) isCONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(8′″) is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(8′″) is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R^(8′″) is CF₃.

The Groups R¹, R^(1′), and R^(1″)

In some embodiments of one or more formulae herein, R¹ is selected fromCN, Cl, C(R¹⁰)₂OH, or F;

In some embodiments of one or more formulae herein, R¹ is selected fromCN, Cl, or F;

In some embodiments of one or more formulae herein, R¹ is selected fromCl, C(R¹⁰)₂OH, or F;

In some embodiments of one or more formulae herein, R¹ is selected fromCN, C(R¹⁰)₂OH, or F;

In some embodiments of one or more formulae herein, R¹ is selected fromCN, Cl, or C(R¹⁰)₂OH;

In some embodiments of one or more formulae herein, R¹ is selected fromC(R¹⁰)₂OH or F;

In some embodiments of one or more formulae herein, R¹ is selected fromCl or C(R¹⁰)₂OH;

In some embodiments of one or more formulae herein, R¹ is selected fromCN or C(R¹⁰)₂OH;

In some embodiments of one or more formulae herein, R¹ is selected fromCN or Cl;

In some embodiments of one or more formulae herein, R¹ is selected fromCN or F;

In some embodiments of one or more formulae herein, R¹ is selected fromCl or F;

In some embodiments of one or more formulae herein, R¹ is CN.

In some embodiments of one or more formulae herein, R¹ is Cl.

In some embodiments of one or more formulae herein, R¹ is C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R¹ is2-hydroxy-2-propyl.

In some embodiments of one or more formulae herein, R¹ is hydroxymethyl.

In some embodiments of one or more formulae herein, R¹ is F.

In some embodiments of one or more formulae herein, R^(1′) is C(O)C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(1′) is CO₂C₁-C₆alkyl;

In some embodiments of one or more formulae herein, R^(1′) is acetyl.

In some embodiments of one or more formulae herein, R^(1′) is1-propanoyl.

In some embodiments of one or more formulae herein, R^(1′) is2-propanoyl.

In some embodiments of one or more formulae herein, R^(1′) is1-butanoyl.

In some embodiments of one or more formulae herein, R^(1′) is2-butanoyl.

In some embodiments of one or more formulae herein, R^(1′) ist-butanoyl.

In some embodiments of one or more formulae herein, R^(1″) is selectedfrom H or C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R^(1″) is selectedfrom H.

In some embodiments of one or more formulae herein, R^(1″) is selectedfrom C(R¹⁰)₂OH.

The Groups R¹⁴, RH^(14′), and RH^(14″)

In some embodiments of one or more formulae herein, R¹⁴ is selected fromH, CN, Cl, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected fromCN, Cl, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected fromH, CN, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected fromH, CN, or Cl.

In some embodiments of one or more formulae herein, R¹⁴ is selected fromH, CN, or Cl.

In some embodiments of one or more formulae herein, R¹⁴ is selected fromH, Cl, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected fromCl or F.

In some embodiments of one or more formulae herein, R¹⁴ is H.

In some embodiments of one or more formulae herein, R¹⁴ is CN.

In some embodiments of one or more formulae herein, R¹⁴ is Cl.

In some embodiments of one or more formulae herein, R¹⁴ is F.

In some embodiments of one or more formulae herein, R^(14′) is selectedfrom CN or F.

In some embodiments of one or more formulae herein, R^(14′) is CN.

In some embodiments of one or more formulae herein, R^(14′) is F.

In some embodiments of one or more formulae herein, R^(14″) is selectedfrom CN, Cl, or F.

In some embodiments of one or more formulae herein, R^(14″) is selectedfrom CN or F.

In some embodiments of one or more formulae herein, R^(14″) is CN.

In some embodiments of one or more formulae herein, R^(14″) is Cl.

In some embodiments of one or more formulae herein, R^(14″) is F.

The Groups R⁹ and R^(9′)

In some embodiments of one or more formulae herein, R⁹ is selected fromC₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl and C₃-C₆heterocycloalkyl.

In some embodiments of one or more formulae herein, R⁹ is selected fromH, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, phenyl,pyridyl, and morpholinyl; wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆cycloalkyl or C₃-C₆ heterocycloalkyl, R⁹ is optionally substituted withone or more substituents each independently selected from ═NR¹³,COOC₁-C₆ alkyl, and CONR¹¹R¹².

In some embodiments of one or more formulae herein, R⁹ is selected fromH, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl,and morpholinyl; wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl orC₃-C₆ heterocycloalkyl, R⁹ is optionally substituted with one or moresubstituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl, andCONR¹¹R¹².

In some embodiments of one or more formulae herein, R⁹ is selected fromC₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, andmorpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected fromH, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected fromH, C₁-C₆ alkyl, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, andmorpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected fromH, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl,and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected fromC(R¹⁰)₂OH, C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected fromC(R¹⁰)₂OH, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁹ is methyl.

In some embodiments of one or more formulae herein, R⁹ is ethyl.

In some embodiments of one or more formulae herein, R⁹ is propyl.

In some embodiments of one or more formulae herein, R⁹ is butyl.

In some embodiments of one or more formulae herein, R⁹ is C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R⁹ is2-hydroxy-2-propyl.

In some embodiments of one or more formulae herein, R⁹ is hydroxymethyl.

In some embodiments of one or more formulae herein, R⁹ isC(R¹⁰)₂NR¹¹R¹².

In some embodiments of one or more formulae herein, R⁹ is C₃-C₆cycloalkyl.

In some embodiments of one or more formulae herein, R⁹ is cyclopropyl.

In some embodiments of one or more formulae herein, R⁹ is cyclobutyl.

In some embodiments of one or more formulae herein, R⁹ is cyclopentyl.

In some embodiments of one or more formulae herein, R⁹ is cyclohexyl.

In some embodiments of one or more formulae herein, R⁹ is phenyl.

In some embodiments of one or more formulae herein, R⁹ is C₃-C₆heterocycloalkyl.

In some embodiments of one or more formulae herein, R⁹ is selected frommorpholinyl or pyridyl.

In some embodiments of one or more formulae herein, R⁹ is morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is N-morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is pyridyl.

In some embodiments of one or more formulae herein, R⁹ is 2-pyridyl.

In some embodiments of one or more formulae herein, R⁹ is 3-pyridyl.

In some embodiments of one or more formulae herein, R⁹ is 4-pyridyl.

In some embodiments of one or more formulae herein, R⁹ is H.

In some embodiments of one or more formulae herein, R⁹ is substitutedwith ═NR¹³.

In some embodiments of one or more formulae herein, R⁹ is substitutedwith COOC₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁹ is substitutedwith CONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, phenyl,pyridyl, and morpholinyl; wherein, when R^(9′) is C₁-C₆ alkyl, C₃-C₆cycloalkyl or C₃-C₆ heterocycloalkyl, R^(9′) is optionally substitutedwith one or more substituents each independently selected from ═NR¹³,COOC₁-C₆ alkyl, and CONR¹¹R¹²;

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl,and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl,and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, andmorpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C₁-C₆ alkyl,) C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, andmorpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl,and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C(R¹⁰)₂OH, C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom C(R¹⁰)₂OH, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^(9′) is methyl.

In some embodiments of one or more formulae herein, R^(9′) is ethyl.

In some embodiments of one or more formulae herein, R^(9′) is propyl.

In some embodiments of one or more formulae herein, R^(9′) is butyl.

In some embodiments of one or more formulae herein, R^(9′) is C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R^(9′) is2-hydroxy-2-propyl.

In some embodiments of one or more formulae herein, R^(9′) ishydroxymethyl.

In some embodiments of one or more formulae herein, R^(9′) isC(R¹⁰)₂NR¹¹R¹².

In some embodiments of one or more formulae herein, R^(9′) is C₃-C₆cycloalkyl.

In some embodiments of one or more formulae herein, R^(9′) iscyclopropyl.

In some embodiments of one or more formulae herein, R^(9′) iscyclobutyl.

In some embodiments of one or more formulae herein, R^(9′) iscyclopentyl.

In some embodiments of one or more formulae herein, R^(9′) iscyclohexyl.

In some embodiments of one or more formulae herein, R^(9′) is phenyl.

In some embodiments of one or more formulae herein, R^(9′) is C₃-C₆heterocycloalkyl.

In some embodiments of one or more formulae herein, R^(9′) is selectedfrom morpholinyl or pyridyl.

In some embodiments of one or more formulae herein, R^(9′) ismorpholinyl.

In some embodiments of one or more formulae herein, R^(9′) isN-morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is 2-pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is 3-pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is 4-pyridyl.

In some embodiments of one or more formulae herein, R^(9′) issubstituted with ═NR¹³.

In some embodiments of one or more formulae herein, R^(9′) issubstituted with COOC₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(9′) issubstituted with CONR¹¹R¹².

The Group R¹⁰

In some embodiments of one or more formulae herein, each R¹⁰ is H.

In some embodiments of one or more formulae herein, each R¹⁰ is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each R¹⁰ is methyl.

In some embodiments of one or more formulae herein, each R¹⁰ is ethyl.

In some embodiments of one or more formulae herein, two R¹⁰ takentogether with the carbon connecting them form a three-to-eight-memberedheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S.

In some embodiments of one or more formulae herein, two R¹⁰ takentogether with the carbon connecting them form a three-membered,six-membered, seven-membered, or eight-membered carbocyclic ring.

In some embodiments, the heterocyclic ring or carbocyclic ring isoptionally substituted with one or more substituents each independentlyselected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³.

In some embodiments of the one or more formulae herein, each R¹⁰ is thesame.

The Groups R¹¹ and R¹²

In some embodiments of one or more formulae herein, R¹¹ is hydrogen.

In some embodiments of one or more formulae herein, R¹¹ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹¹ is CO₂R¹⁵.

In some embodiments of one or more formulae herein, R¹¹ is CONR¹⁷NR¹⁸.

In some embodiments of one or more formulae herein, R¹² is hydrogen.

In some embodiments of one or more formulae herein, R¹² is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹² is CO₂R¹⁵.

In some embodiments of one or more formulae herein, R¹² is CONR¹⁷NR¹⁸.

The Groups R¹³, R¹⁵, R¹⁷ and R¹⁸

In some embodiments of one or more formulae herein, R¹³ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁵ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁷ is hydrogen.

In some embodiments of one or more formulae herein, R¹⁷ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁸ is hydrogen.

In some embodiments of one or more formulae herein, R¹⁸ is C₁-C₆ alkyl.

The Group R¹⁶

In some embodiments of one or more formulae herein, R¹⁶ is hydrogen.

In some embodiments of one or more formulae herein, R¹⁶ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁶ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R¹⁶ is NR¹¹R¹².

In some embodiments of one or more formulae herein, R¹⁶ is oxo.

In some embodiments of one or more formulae herein, R¹⁶ is C₁═NR¹³.

Additional Embodiments

In some embodiments of one or more formulae herein:

if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl;R^(H) is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments of one or more formulae herein:

if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl; R¹is H, then R⁸ is not F or Cl.

In some embodiments the compound of any of the formulae herein is not acompound disclosed in any of Examples 1-150 of patent publicationWO2001/019390, which are incorporated by reference herein.

In some embodiments the compound of any of the formulae herein is not acompound disclosed in any of Examples 1-130 of patent publication WO98/32733, which are incorporated by reference herein.

In some embodiments the compound of any of the formulae herein is not acompound disclosed in any of the Examples at [00123] of patentpublication WO2016/131098, which are incorporated by reference herein.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;-   R² is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy;-   R³ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy;-   R⁴ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy    and is the same as R²;-   R⁵ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy    and is the same as R³;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    five-membered ring A and R⁴ and R⁵ taken together with the carbons    connecting them form a five-membered ring B, wherein ring A is

and ring B is

-   wherein each R⁶ in each ring is the same and is H or C₁-C₆ alkyl,    and each R⁷ each ring is the same and is H or C₁-C₆ alkyl;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   each R¹⁰ is the same and is selected from H and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;-   R² is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy;-   R³ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy;-   R⁴ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy    and is the same as R²;-   R⁵ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy    and is the same as R³;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    five-membered ring A and R⁴ and R⁵ taken together with the carbons    connecting them form a five-membered ring B, wherein ring A is

and ring B is

wherein each R⁶ in each ring is the same and is H or C₁-C₆ alkyl, andeach R⁷ in each ring is the same and is H or C₁-C₆ alkyl;

-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   each R¹⁰ is the same and is selected from H and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, a compound of Formula I is a compound of FormulaI(A):

or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and le are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and    C₃-C₆ cycloalkyl;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, a compound of Formula I is a compound of FormulaI(A):

or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

-   wherein-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and    C₃-C₆ cycloalkyl;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, the compound of Formula I(A) is a compound ofFormula I(A)-i:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I(A) (including I(A)-i),R² and R⁴ are each isopropyl.

In some embodiments, the compound of Formula I(A) is a compound ofFormula I(A)-ii:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I(A) (including I(A)-ii),R³ and R⁵ are each isopropyl.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R⁸ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R⁸ is CN.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R⁸ is Cl.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R⁸ is F.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R⁸ is CO₂C₁-C₆ alkyl.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R⁸ is CONH_(2.)

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹ is CN.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹ is Cl.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹ is F.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹⁴ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹⁴ is CN.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹⁴ is Cl.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹⁴ is F.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹⁴ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-iand I(A)-ii), R¹⁰ is CH₃.

In some embodiments of the compound of Formula I(A), ring A is acarbocyclic ring and n1 is 3.

In some embodiments of the compound of Formula I(A), ring A is acarbocyclic ring and n1 is 4.

In some embodiments of the compound of Formula I(A), ring A is aheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S and n1 is 3.

In some embodiments of the compound of Formula I(A), ring A is aheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S and n1 is 4.

In some embodiments of the compound of Formula I(A), ring B is acarbocyclic ring and n2 is 3.

In some embodiments of the compound of Formula I(A), ring B is acarbocyclic ring and n2 is 4.

In some embodiments of the compound of Formula I(A), ring B is aheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S and n2 is 3.

In some embodiments of the compound of Formula I(A), ring B is aheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S and n2 is 4.

In some embodiments, the compound of Formula I is a compound of FormulaI(B):

wherein

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;-   wherein-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and    C₃-C₆ cycloalkyl;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   and each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl.

In some embodiments, the compound of Formula I(B) is a compound ofFormula I(B)-i:

In some embodiments, the compound of Formula I(B) is a compound ofFormula I(B)-ii:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I(B) is a compound ofFormula I(B)-iii:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), each R⁶ is hydrogen.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-ii and I(B)-iii), each R⁶ is hydrogen and each R⁷ is hydrogen.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R⁸ is H.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R⁸ is CN.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R⁸ is Cl.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R⁸ is F.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R¹ is H.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R¹ is CN.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R¹ is Cl.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-i, I(B)ii and I(B)-iii), R¹ is F.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-ii, R⁹ is C₁-C₆ alkyl.

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-ii, R⁹ is C(R¹⁰)₂OH,

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-ii, R⁹ is C(R¹⁰)₂NR¹¹R¹².

In some embodiments of the compound of Formula I(B) (including FormulaI(B)-ii, R⁹ is C₃-C₆ cycloalkyl.

In some embodiments of the compound of Formula I(B) (including I(B)-iand I(B)-ii), R¹⁰ is H.

In some embodiments of the compound of Formula I(B) (including I(B)-iand I(B)-iii), R¹⁰ is CH₃.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring A is a carbocyclic ring and n1 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring A is a carbocyclic ring and n1 is 4.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring A is a heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S and n1 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring A is a heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S and n1 is 4.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring B is a carbocyclic ring and n2 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring B is a carbocyclic ring and n2 is 4.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring B is a heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S and n2 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i),ring B is a heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S and n2 is 4.

In some embodiments, the compound of Formula II is a compound of FormulaIIa:

In some embodiments, the compound of Formula II is a compound of FormulaIIb:

In some embodiments, the compound of Formula II is a compound of FormulaIIc:

In some embodiments, the compound of Formula II is a compound of FormulaIId:

In some embodiments, the compound of Formula II is a compound of FormulaIIe:

Exemplary embodiments provided herein include the following embodiments1)-81):

-   -   1) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²; oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹²; C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹° is the same and is H or C₁-C₆ alkyl;-   or two R¹⁰ taken together with the carbon connecting them form a    three-to-eight-membered heterocyclic ring containing 1 or 2    heteroatoms independently selected from O, N, and S, or a    three-membered, six-membered, seven-membered, or eight-membered    carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring    is optionally substituted with one or more substituents each    independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²;    oxo, and ═NR¹³;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl,-   CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl;-   each R¹⁶ is the same or different and is selected from H, C₁-C₆    alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.    -   2) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl,-   CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl;-   each R¹⁶ is the same or different and is selected from H, C₁-C₆    alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.    -   3) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl,-   CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl; each R¹⁶ is the same or different and    is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and    ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

4) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   or when X¹ is NH, X¹ and R² taken together with the atoms connecting    them form a four-to-seven-membered heterocyclic ring optionally    substituted with one or more R¹⁶;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,    wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   R¹³ is C₁-C₆ alkyl;-   each of R¹¹ and R¹² at each occurrence is independently selected    from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸;-   R¹⁵ is C₁-C₆ alkyl;-   each of R¹⁷ and R¹⁸ at each occurrence is independently selected    from hydrogen and C₁-C₆ alkyl;-   each R¹⁶ is the same or different and is selected from H, C₁-C₆    alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.    -   5) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.    -   6) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O;-   Y is N or CR⁸;-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈    cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl;-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆    cycloalkyl and C₃-C₆ heterocycloalkyl;-   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆    heterocycloalkyl, R⁹ is optionally substituted with one or more    substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,    and CONR¹¹R¹²;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.    -   7) The compound of any one of claims 1 to 4, wherein X¹ is NH.    -   8) The compound of any one of claims 1 to 4, wherein X¹ is O.    -   9) The compound of claim 1, wherein X¹ and R² taken together        with the atoms connecting them form a four-to-seven-membered        heterocyclic ring optionally substituted with one or more R¹⁶.    -   10) The compound of claim 1, wherein X¹ and R⁴ taken together        with the atoms connecting them form a four-to-seven-membered        heterocyclic ring optionally substituted with one or more oxo.    -   11) The compound of claim 1, wherein X¹ and R² taken together        with the atoms connecting them form a four-to-seven-membered        heterocyclic ring optionally substituted with one or more C₁-C₆        alkyl .    -   12) The compound of claim 1, wherein X¹ and R⁴ taken together        with the atoms connecting them form a four-to-seven-membered        heterocyclic ring optionally substituted with one or more        methyl.    -   13) The compound of claim 1, wherein X¹ and R⁴ taken together        with the atoms connecting them form a four-to-seven-membered        heterocyclic ring optionally substituted with one or more C₁-C₆        alkoxy.    -   14) The compound of any one of claims 1 to 13, wherein Y is CR⁸.    -   15) The compound of any one of claims 1 to 13, wherein Y is N.    -   16) The compound of claim 14 or 15, wherein R² is hydrogen.    -   17) The compound of claim 14 or 15, wherein R² is C₁-C₆ alkyl        optionally substituted with hydroxy.    -   18) The compound of claim 14 or 15, wherein R² is isopropyl.    -   19) The compound of claim 14 or 15, wherein R² is methyl.    -   20) The compound of any one of claims 14 to 19, wherein R³ is        hydrogen.    -   21) The compound of any one of claims 14 to 19, wherein R³ is        C₁-C₆ alkyl optionally substituted with hydroxy.    -   22) The compound of any one of claims 14 to 19, wherein R³ is        isopropyl.    -   23) The compound of any one of claims 14 to 19, wherein R³ is        methyl.    -   24) The compound of any one of claims 14 to 23, wherein R⁴ is        hydrogen.    -   25) The compound of any one of claims 14 to 23, wherein R⁴ is        C₁-C₆ alkyl optionally substituted with hydroxy.    -   26) The compound of any one of claims 14 to 23, wherein R⁴ is        isopropyl.    -   27) The compound of any one of claims 14 to 23, wherein R⁴ is        methyl.    -   28) The compound of any one of claims 14 to 27, wherein R⁵ is        hydrogen.    -   29) The compound of any one of claims 14 to 27, wherein R⁵ is        C₁-C₆ alkyl optionally substituted with hydroxy.    -   30) The compound of any one of claims 14 to 27, wherein R⁵ is        isopropyl.    -   31) The compound of any one of claims 14 to 27, wherein R⁵ is        methyl.    -   32) The compound of any one of claims 14 to 15 or 24 to 31,        wherein R² and R³ taken together with the carbons connecting        them form ring A.    -   33) The compound of any one of claim 14 to 24 or 32, wherein R²        and R³ taken together with the carbons connecting them form ring        B.    -   34) The compound of claim 32 or 33, wherein ring A is the same        as ring B.    -   35) The compound of claim 32, 33 or 34, wherein ring A is

-   -   36) The compound of any one of claims 32 to 35, wherein ring B        is

-   -   37) The compound of claim 35 or 36, wherein n1 is 3.    -   38) The compound of claim 35 or 36, wherein n1 is 4.    -   39) The compound of any one of claims 35 to 38, wherein n2 is 3.    -   40) The compound of any one of claims 35 to 38, wherein n2 is 4.    -   41) The compound of any one of claims 35 to 40, wherein R⁶ is H.    -   42) The compound of any one of claims 1 to 14 or 16 to 41,        wherein R⁸ is H.    -   43) The compound of any one of claims 1 to 14 or 16 to 41,        wherein R⁸ is CN.    -   44) The compound of any one of claims 1 to 14 or 16 to 41,        wherein R⁸ is Cl.    -   45) The compound of any one of claims 1 to 14 or 16 to 41,        wherein R⁸ is F.    -   46) The compound of any one of claims 1 to 14 or 16 to 41,        wherein R⁸ is C₁-C₆ alkyl.    -   47) The compound of any one of claims 1 to 14 or 16 to 41,        wherein R⁸ is C₁-C₆ haloalkyl.    -   48) The compound of any one of claims 1 to 14 or 16 to 41,        wherein R⁸ is CF₃.    -   49) The compound of any one of claims 1 to 48, wherein R¹ is H.    -   50) The compound of any one of claims 1 to 48, wherein R¹ is CN.    -   51) The compound of any one of claims 1 to 48, wherein R¹ is Cl.    -   52) The compound of any one of claims 1 to 48, wherein R¹ is F.    -   53) The compound of any one of claims 1 to 52, wherein R¹⁴ is H.    -   54) The compound of any one of claims 1 to 52, wherein R¹⁴is CN.    -   55) The compound of any one of claims 1 to 52, wherein R¹⁴ is        Cl.    -   56) The compound of any one of claims 1 to 52, wherein R¹⁴ is F.    -   57) The compound of any one of claims 1 to 56, wherein R⁹ is        C(R¹⁰)₂OH.    -   58) The compound of any one of claims 1 to 56, wherein R⁹ is        C(R¹⁰)₂NR¹¹R¹².    -   59) The compound of any one of claims 1 to 56, wherein R⁹ is        C₁-C₆ alkyl.    -   60) The compound of any one of claims 1 to 56, wherein R⁹ is        C₃-C₆ cycloalkyl.    -   61) The compound of any one of claims 1 to 58, wherein each R¹⁰        is H.    -   62) The compound of any one of claims 1 to 58, wherein each R¹⁰        is C₁-C₆ alkyl.    -   63) The compound of any one of claims 1 to 58, wherein each R¹⁰        is methyl.    -   64) The compound of any one of claims 1 to 58, wherein two R¹⁰        taken together with the carbon connecting them form a        three-to-eight-membered heterocyclic ring containing 1 or 2        heteroatoms independently selected from O, N, and S.    -   65) The compound of any one of claims 1 to 58, wherein two R¹⁰        taken together with the carbon connecting them form a        three-membered, six-membered, seven-membered, or eight-membered        carbocyclic ring.    -   66) The compound of any one of claim 64 or 65, wherein formed by        the two R¹⁰ is optionally substituted with one or more        substituents each independently selected from H, C₁-C₆ alkyl,        C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³.    -   67) The compound of claim 1, wherein each R¹¹ is hydrogen.    -   68) The compound of claim 1, wherein each R¹¹ is C₁-C₆ alkyl.    -   69) The compound of claims 1 or 67 to 68, wherein each R¹² is        hydrogen.    -   70) The compound of claims 1 or 67 to 68, wherein each R¹² is        C₁-C₆ alkyl.    -   71) The compound of any one of claims 1 to 4 or 10 to 13,        wherein each R¹⁶ is hydrogen.    -   72) The compound of any one of claims 1 to 71, wherein if R² and        R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl; R¹⁴ is        H; and R¹ is H, then R⁸ is not F or Cl.    -   73) The compound of any one of claims 1 to 71, wherein if R² and        R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl; and R¹        is H,        -   then R⁸ is not F or Cl.    -   74) A compound of any one of claims 1 to 4, wherein the compound        is a compound of Formula I(A):

-   -   -   or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸;

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;

-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;

-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,

-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,

-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,

-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   ml is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and    C₃-C₆ cycloalkyl;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;    -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each        R¹⁰ is C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or        Cl.    -   75) A compound of any one of claims 1 to 4, wherein the compound        is a compound of Formula I(A):

-   -   -   or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸;

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;

-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl    optionally substituted with hydroxy;

-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and    that R² and R⁴ are not both hydroxymethyl;

-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A,

-   or R⁴ and R⁵ taken together with the carbons connecting them form a    four-membered to seven-membered ring B,

-   or R² and R³ taken together with the carbons connecting them form a    four-membered to seven-membered ring A and R⁴ and R⁵ taken together    with the carbons connecting them form a four-membered to    seven-membered ring B,

-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and    C₃-C₆ cycloalkyl;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl;-   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is    C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.    -   76) A compound of any one of claims 1 to 4 or 74 to 75, wherein        the compound is a compound of Formula I(A)-i:

-   -   -   or a pharmaceutically acceptable salt thereof.

    -   77) A compound of any one of claims 1 to 4 or 74 to 76, wherein        the compound is a compound of Formula I(A)-ii:

-   -   -   or a pharmaceutically acceptable salt thereof.

    -   78) A compound of any one of claims 1 to 4, wherein the compound        is a compound of Formula I(B):

wherein

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;-   wherein-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or    2 heteroatoms independently selected from O, N, and S;-   n1 is from 2 to 5;-   m1 is from 1 to 10;-   wherein ring B is a carbocyclic ring or a heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   n2 is from 2 to 5;-   m2 is from 1 to 10;-   wherein each R⁶ in each ring is the same or different and is    selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R^(12,) oxo, and    ═NR¹³;-   or two R⁶ taken together with the atom or atoms connecting them form    a 3-to-8-membered carbocyclic or saturated heterocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N, and    S;-   R¹ is selected from H, CN, Cl, or F;-   R¹⁴ is selected from H, CN, Cl, or F;-   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and    C₃-C₆ cycloalkyl;-   each R¹⁰ is the same and is H or C₁-C₆ alkyl;-   and each of R¹¹, R¹² and R¹³ at each occurrence is independently    selected from hydrogen and C₁-C₆ alkyl.    -   79) A compound of any one of claim 1 to 4 or 78, wherein the        compound is a compound of Formula I(B)-i:

-   -   -   or a pharmaceutically acceptable salt thereof

    -   80) A compound of any one of claim 1 to 4 or 78, wherein the        compound is a compound of Formula I(B)-ii:

-   -   -   or a pharmaceutically acceptable salt thereof.

    -   81)A compound of any one of claim 1 to 4 or 78, wherein the        compound is a compound of Formula I(B)-iii:

-   -   -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound selected from thegroup consisting of compounds in Table 1 below, and NLRP1 antagonistactivity is shown for compounds for which data is available. <1μM=“++++”, ≥1 and <5 μM=“++++”, ≥5 and <15 μM=“++”, ≥15 and <35 μM=“+”.

TABLE 1 hNLRP3 (THP- 1, IL-1β) Average IC₅₀ Compound Structure (μM) 101

+++ 102

+++ 103

+++ 104

105

+++ 106

107

+++ 108

+++ 109

+++ 110

++++ 111

++++ 112

++++ 113

++++ 114

++++ 115

++++ 116

++++ 117

++++ 118

119

120

++++ 121

122

123

++++ 124

+++ 125

+++ 126

++++ 127

++++ 128

131

++++ 132

135

136

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound selected from thegroup consisting of compounds in Table 2 below, and NLRP1 antagonistactivity is shown for compounds for which data is available. <1μM=“++++”; >1 and <5 μM=“+++”; >5 and <15 μM=“++”; >15 and <35 μM=“+”.

TABLE 2 hNLRP3 (THP- 1, IL-1β) Average IC₅₀ Compound Structure (μM) 137

++++ 138

++++ 141

++++ 142

++++ 143

++++ 144

++++ 145

++++ 146

++++ 147

++++ 148

+++ 149

+++ 150

+++ 151

+++ 153

+++ 154

+++ 155

+++ 157

+++ 158

++ 159

++ 160

++++ 161

++++ 162

++++ 163

++++ 164

++++ 165

++++ 166

++++ 167

++++ 168

+++ 169

+++ 170

+++ 171

+++

and pharmaceutically acceptable salts thereof.

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that modulates(e.g., antagonizes) NLRP1 or NLRP3 or both NLRP1 and NLRP3, or apharmaceutically acceptable salt and/or hydrate, and/or cocrystal,and/or drug combination thereof) is administered as a pharmaceuticalcomposition that includes the chemical entity and one or morepharmaceutically acceptable excipients, and optionally one or moreadditional therapeutic agents as described herein.

In some embodiments, the chemical entities can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%-100% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press,London, UK. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intraci sternal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumoral, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal. In certain embodiments, apreferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,sub-cutaneous, or even intraperitoneal routes. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for use to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified. The preparationof such formulations will be known to those of skill in the art in lightof the present disclosure.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil, or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that it may be easily injected. It also should be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi.

The carrier also can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion, and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques, which yield a powder of the active ingredient, plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effectof Intratumoral Injection on the Biodistribution and the TherapeuticPotential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788-795.

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carbopol,methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate,isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) ,lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceuticalcomposition thereof are suitable for local delivery to the digestive orGI tract by way of oral administration (e.g., solid or liquid dosageforms.).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules sterility is notrequired. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include oneor more components that chemically and/or structurally predispose thecomposition for delivery of the chemical entity to the stomach or thelower GI; e.g., the ascending colon and/or transverse colon and/ordistal colon and/or small bowel. Exemplary formulation techniques aredescribed in, e.g., Filipski, K. J., et al., Current Topics in MedicinalChemistry, 2013, 13, 776-802, which is incorporated herein by referencein its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill(Intec Pharma), floating capsules, and materials capable of adhering tomucosal walls.

Other examples include lower-GI targeting techniques. For targetingvarious regions in the intestinal tract, several enteric/pH-responsivecoatings and excipients are available. These materials are typicallypolymers that are designed to dissolve or erode at specific pH ranges,selected based upon the GI region of desired drug release. Thesematerials also function to protect acid labile drugs from gastric fluidor limit exposure in cases where the active ingredient may be irritatingto the upper GI (e.g., hydroxypropyl methylcellulose phthalate series,Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate,hydroxypropyl methylcellulose acetate succinate, Eudragit series(methacrylic acid-methyl methacrylate copolymers), and Marcoat). Othertechniques include dosage forms that respond to local flora in the GItract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of anyof the following: viscogens (e.g., Carboxymethylcellulose, Glycerin,Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic(triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkoniumchloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zincchloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositionsdescribed herein can include one or more one or more of the following:lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-basednanoparticles or microparticles, and nanoporous particle-supported lipidbilayers.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Determination of the proper dosage for a particularsituation can be determined by one skilled in the medical arts. Thetotal daily dosage may be divided and administered in portionsthroughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered ata dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0. 1mg/Kg to about 200 mg/Kg; from about 0. 1 mg/Kg to about 150 mg/Kg; fromabout 0. 1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50mg/Kg;

from about 0. 1 mg/Kg to about 10 mg/Kg; from about 0. 1 mg/Kg to about5 mg/Kg; from about 0. 1 mg/Kg to about 1 mg/Kg; from about 0. 1 mg/Kgto about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose or as two or more divided doses) or non-daily basis (e.g.,every other day, every two days, every three days, once weekly, twiceweeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compounddescribed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 1 1 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1months, 12 months, or more. In an embodiment, a therapeutic compound isadministered to an individual for a period of time followed by aseparate period of time. In another embodiment, a therapeutic compoundis administered for a first period and a second period following thefirst period, with administration stopped during the second period,followed by a third period where administration of the therapeuticcompound is started and then a fourth period following the third periodwhere administration is stopped. In an aspect of this embodiment, theperiod of administration of a therapeutic compound followed by a periodwhere administration is stopped is repeated for a determined orundetermined period of time. In a further embodiment, a period ofadministration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition,disease or disorder in which a decrease or increase in NLRP1 or NLRP3 orboth NLRP1 and NLRP3 activity (e.g., an increase, e.g., NLRP1/3signaling) contributes to the pathology and/or symptoms and/orprogression of the condition, disease or disorder are provided,comprising administering to a subject an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

Indications

In some embodiments, the condition, disease or disorder is selectedfrom: inappropriate host responses to infectious diseases where activeinfection exists at any body site, such as septic shock, disseminatedintravascular coagulation, and/or adult respiratory distress syndrome;acute or chronic inflammation due to antigen, antibody and/or complementdeposition; inflammatory conditions including arthritis, cholangitis,colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis,myocarditis, pancreatitis, pericarditis, reperfusion injury andvasculitis, immune-based diseases such as acute and delayedhypersensitivity, graft rejection, and graft-versus-host disease;auto-immune diseases including Type 1 diabetes mellitus and multiplesclerosis. For example, the condition, disease or disorder may be aninflammatory disorder such as rheumatoid arthritis, osteoarthritis,septic shock, COPD and periodontal disease.

In some embodiments, the condition, disease or disorder is an autoimmunediseases. Non limiting examples include rheumatoid arthritis, systemiclupus erythematosus, multiple sclerosis, inflammatory bowel diseases(IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), whichare chronic inflammatory conditions with polygenic susceptibility. Incertain embodiments, the condition is an inflammatory bowel disease. Incertain embodiments, the condition is Crohn's disease, autoimmunecolitis, iatrogenic autoimmune colitis, ulcerative colitis, colitisinduced by one or more chemotherapeutic agents, colitis induced bytreatment with adoptive cell therapy, colitis associated by one or morealloimmune diseases (such as graft-vs-host disease, e.g., acute graftvs. host disease and chronic graft vs. host disease), radiationenteritis, collagenous colitis, lymphocytic colitis, microscopiccolitis, and radiation enteritis. In certain of these embodiments, thecondition is alloimmune disease (such as graft-vs-host disease, e.g.,acute graft vs. host disease and chronic graft vs. host disease), celiacdisease, irritable bowel syndrome, rheumatoid arthritis, lupus,scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, andmucositis (e.g., oral mucositis, esophageal mucositis or intestinalmucositis).

In some embodiments, the condition, disease or disorder is selected frommetabolic disorders such as type 2 diabetes, atherosclerosis, obesityand gout, as well as diseases of the central nervous system, such asAlzheimer's disease and multiple sclerosis and Amyotrophic

Lateral Sclerosis and Parkinson disease, lung disease, such as asthmaand COPD and pulmonary idiopathic fibrosis, liver disease, such as NASHsyndrome, viral hepatitis and cirrhosis, pancreatic disease, such asacute and chronic pancreatitis, kidney disease, such as acute andchronic kidney injury, intestinal disease such as Crohn's disease andUlcerative Colitis, skin disease such as psoriasis, musculoskeletaldisease such as scleroderma, vessel disorders, such as giant cellarteritis, disorders of the bones, such as osteoarthritis, osteoporosisand osteopetrosis disorders, eye disease, such as glaucoma and maculardegeneration, diseases caused by viral infection such as HIV and AIDS,autoimmune diseases such as rheumatoid arthritis, systemic Lupuserythematosus, autoimmune thyroiditis; Addison's disease, and perniciousanemia, cancer and aging.

In some embodiments, the condition, disease or disorder is acardiovascular indication. In some embodiments, the condition, diseaseor disorder is myocardial infraction. In some embodiments, thecondition, disease or disorder is stroke.

In some embodiments, the condition, disease or disorder is obesity.

In some embodiments, the condition, disease or disorder is Type 2Diabetes.

In some embodiments, the condition, disease or disorder is NASH.

In some embodiments, the condition, disease or disorder is Alzheimer'sdisease.

In some embodiments, the condition, disease or disorder is gout.

In some embodiments, the condition, disease or disorder is SLE.

In some embodiments, the condition, disease or disorder is rheumatoidarthritis.

In some embodiments, the condition, disease or disorder is IBD.

In some embodiments, the condition, disease or disorder is multiplesclerosis.

In some embodiments, the condition, disease or disorder is COPD.

In some embodiments, the condition, disease or disorder is asthma.

In some embodiments, the condition, disease or disorder is scleroderma.

In some embodiments, the condition, disease or disorder is pulmonaryfibrosis.

In some embodiments, the condition, disease or disorder is age relatedmacular degeneration (AMD).

In some embodiments, the condition, disease or disorder is cysticfibrosis.

In some embodiments, the condition, disease or disorder is Muckle Wellssyndrome.

In some embodiments, the condition, disease or disorder is familial coldautoinflammatory syndrome (FCAS).

In some embodiments, the condition, disease or disorder is chronicneurologic cutaneous and articular syndrome.

Combination therapy

This disclosure contemplates both monotherapy regimens as well ascombination therapy regimens.

In some embodiments, the methods described herein can further includeadministering one or more additional therapies (e.g., one or moreadditional therapeutic agents and/or one or more therapeutic regimens)in combination with administration of the compounds described herein.

In certain embodiments, the second therapeutic agent or regimen isadministered to the subject prior to contacting with or administeringthe chemical entity (e.g., about one hour prior, or about 6 hours prior,or about 12 hours prior, or about 24 hours prior, or about 48 hoursprior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen isadministered to the subject at about the same time as contacting with oradministering the chemical entity. By way of example, the secondtherapeutic agent or regimen and the chemical entity are provided to thesubject simultaneously in the same dosage form. As another example, thesecond therapeutic agent or regimen and the chemical entity are providedto the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen isadministered to the subject after contacting with or administering thechemical entity (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedto NLRP3 polymorphism.

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedto NLRP3 where polymorphism is a gain of function

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedto NLRP3 polymorphism found in CAPS syndromes.

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedNLRP3 polymorphism where the polymorphism is VAR_014104 (R262W)

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP3 activity, such as an indication relatedNLRP3 polymorphism where the polymorphism is a natural variant reportedin http://www.uniprot.org/uniprot/Q96P20

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP1 activity, such as an indication relatedNLRP1 polymorphism.

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP1 activity, such as an indication relatedto NLRP1 where polymorphism is a gain of function

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP1 activity, such as an indication relatedNLRP1 polymorphism found in vitiligo Vitiligo-Associated AutoimmuneDisease.

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP1 activity, such as an indication relatedwhere NLRP1 polymorphism is VAR_033239 (L155H)

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP1 activity, such as an indication relatedwhere NLRP1 polymorphism is a natural variant reported inhttp://www.uniprot.org/uniprot/Q9C000

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of treatment foran indication related to NLRP1/3 activity, such as an indication relatedto point mutation of NLRP1/3 signaling.

Compound Preparation and Biological Assays

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the compounds described herein are known in the art andinclude, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and R G M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed.,John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995), and subsequent editions thereof. Suitable methodsfor the preparation of the compounds herein are also disclosed in patentpublications EP 1214087, WO 2001/019390, and WO 98/32733, each of whichis incorporated by reference in its entirety.

Scheme 1 shows an example of a method of preparation of compoundsdisclosed herein:

-   The following abbreviations have the indicated meanings:-   ACN=acetonitrile-   AcOH=acetic acid-   BINAP=(±)-2,2′-(diphenylphosphino)-1,1′-binaphthyl-   BTC=trichloromethyl chloroformate-   DBU=1,8-diazabicycloundec-7-ene-   DCM=dichloromethane-   DMEDA=N,N′-dimethylethylenediamine-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   Et=ethyl-   EtOH=ethanol-   LC-MS=liquid chromatography-mass spectrometry-   Me=methyl-   MeOH=methanol-   NBS=N-bromosuccinimide-   NCS=N-chlorosuccinimide-   NMR=nuclear magnetic resonance-   Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium-   Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium-   Pd(PPh₃)₄=tetrakis(triphenylphosphine)Palladium(0)-   Ph=phenyl-   HPLC=high performance liquid chromatography-   Py=pyridine-   RT=room temperature-   t-Bu=tert-butyl-   TEA=triethylamine-   THF=tetrahydrofuran-   TLC=thin layer chromatography

Materials and Methods

The progress of reactions was often monitored by TLC or LC-MS. Theidentity of the products was often confirmed by LC-MS. The LC-MS wasrecorded using one of the following methods.

Method A: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uLinjection, 1.5 mL/min flow rate, 90-900 amu/scan range, 190-400 nm UVrange, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA)and water (0.05% TFA), 2 minute total run time.

Method B: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection,1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95%(1.1 min), 95% (0.6 min) gradient with ACN and water (0.5% N₄HCO₃), 2minute total run time.

Method C: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uLinjection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UVrange, 5-100% (2.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA)and water (0.05% TFA), 3 minute total run time.

Method D: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection,1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95%(2.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH₄HCO₃), 3minute total run time.

The final targets were purified by Prep-HPLC. The Prep-HPLC was carriedout using the following method.

Method E: Pre-HPLC: Column, XBridge Shield RP18 OBD (19×250 mm, 10 um);mobile phase, Water (10 mmol/L NH₄HCO₃) and ACN, UV detection 254/210nm.

NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD™ 300,AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™400, AVANCE III 400, B-ACS™ 120.

PREPARATIVE EXAMPLES Preparative Example 1 Compound 131

1. Synthesis of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

Into a 50-mL round-bottom flask, was placed a solution of1,2,3,5,6,7-hexahydro-s-indacen-4-amine (100 mg, 0.58 mmol, 1.00 equiv)in tetrahydrofuran (10 mL). To the solution were added TEA (29 mg, 0.29mmol, 0.50 equiv) and ditrichloromethyl carbonate (51.5 mg, 0.17 mmol,0.30 equiv). The resulting solution was stirred for 1 h at 60° C. Theresulting mixture was concentrated under vacuum. This resulted in 110 mg(crude) of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene as a whitesolid.

2. Synthesis of1-[[2-fluoro-5-(2-hydroxypropan-2-yl)benzene]sulfonyl]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea(Compound 131)

Into a 50-mL 3-necked round-bottom flask, was placed a solution of2-fluoro-5-(2-hydroxypropan-2-yl)benzene-1-sulfonamide (130 mg, 0.56mmol, 1.00 equiv) in tetrahydrofuran (10 mL). To the solution were addedDBU (127.21 mg, 0.84 mmol, 1.50 equiv) and4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.55 mmol, 0.99equiv). The resulting solution was stirred for 5 h at room temperature.The resulting mixture was concentrated under vacuum. The crude productwas purified by Prep-HPLC with the following conditions (HPLC-10):Column, X Bridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile phase,Water (10 mmol/L NH₄HCO₃) and ACN (30% ACN up to 51% in 6 min);Detector, UV 254/220 nm. This resulted in 46 mg (19%) of1-[[2-fluoro-5-(2-hydroxypropan-2-yl)benzene]sulfonyl]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureaas a white solid.

LC-MS: (ES, m/z): [M+H]⁺=433.2.

H-NMR: (DMSO-d₆, 400 MHz, ppm): δ 7.97-7.96 (m, 2H), 7.69 (brs, 1H),7.34-7.29 (m, 1H), 6.89 (s, 1H), 5.28 (s, 1H), 2.76 (t, J=7.2 Hz, 4H),2.57-2.52 (m, 4H), 1.93-1.89 (m, 4H), 1.41 (s, 6H).

Schemes of final targets: Schemes 2-5 illustrate several conditions usedfor coupling of amine 1 and sulfonamide 2 to afford sulfonyl urea 3

Schemes of Sulfonamides Intermediates: Schemes 6-12 illustrate thepreparation of sulfonamide intermediates.

3-Chloro-5-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1:3-Chloro-5-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 100-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen, was placed a solution of methyl3-chloro-5-sulfamoylbenzoate (579 mg, 2.32 mmol) in THF (20 mL). Thiswas followed by the addition of MeMgBr/THF (3 M, 3.5 mL) dropwise withstirring at 0° C. The resulting solution was stirred for 12 h at RT andthen was quenched by the addition of 20 mL of NH₄Cl (sat.). The solutionwas extracted with 3×20 mL of ethyl acetate and the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:3 to1:1). This resulted in 415 mg (72%) of the title compound as a lightyellow solid. MS-ESI: 248.0, 250.0 (M−1).

3 -(2-Hydroxypropan-2-yl)benzenesulfonamide Step 1: Methyl3-sulfamoylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl3-(chlorosulfonyl)benzoate (2 g, 8.5 mmol) in DCM (35 mL). To the abovewas added a saturated solution of ammonia in DCM (15 mL). The resultingsolution was stirred for 2 hat RT and then was concentrated undervacuum. The residue was applied onto a silica gel column and eluted withethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 1.753 g(93%) of the title compound as a white solid. MS-ESI: 214.0 (M−1).

Step 2: 3 -(2-Hydroxypropan-2-yl)benzenesulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen, was placed a solution of methyl 3-sulfamoylbenzoate(1.753 g, 8.14 mmol) in THF (70 mL). This was followed by the additionof MeMgBr/THF (3 M, 12.2 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 12 h at RT and then was quenched bythe addition of 30 mL of NH₄Cl (sat.). The resulting solution wasextracted with 5×30 mL of ethyl acetate and the organic layers combinedand concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). Thisresulted in 1.642 g (94%) of the title compound as a white solid.MS-ESI: 214.1 (M−1).

TABLE 3 The Intermediate in the following Table was prepared using thesimilar procedures for converting compound 2 to Intermediate 2 shown inScheme 7. Intermediate # Structure IUPAC Name Mass Spec [M − H]⁻Intermediate 19

4-(2-hydroxypropan-2-yl) benzenesulfonamide 214.1

3-Cyano-5-(2-hydroxypropan-2-yl)benzenesulfonamide

Steps 1-2 used similar procedures for converting compound 2 toIntermediate 2 shown in Scheme 6 to afford compound 6. MS-ESI: 292.0(M−1).

Step 3: 3-Cyano-5-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 50-mL round-bottom flask purged with and maintained undernitrogen, was placed 3-bromo-5-(2-hydroxypropan-2-yl)benzenesulfonamide(343 mg, 1.17 mmol), DMF (8 mL), CuCN (157 mg, 1.75 mmol), t-BuOK (13mg, 0.12 mmol), Pd(dppf)Cl₂ (171 mg, 0.23 mmol), and Pd(PPh₃)₄ (138 mg,0.12 mmol). The resulting solution was stirred for 12 h at 120° C. andthen was quenched by the addition of 10 mL of NH₄Cl (sat.). Theresulting solution was extracted with 3×20 mL of ethyl acetate and theorganic layers combined and dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). Thisresulted in 159 mg (57%) of the title compound as a white solid. MS-ESI:239.1 (M−1).

2-Fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1: Methyl3-(chlorosulfonyl)-4-fluorobenzoate

Into a 100-mL round-bottom flask, was placed methyl3-amino-4-fluorobenzoate (1 g, 5.91 mmol), HCl (6 M, 10 mL). This wasfollowed by the addition of a solution of NaNO₂ (630 mg, 9.13 mmol) inwater (2 mL) dropwise with stirring at 0° C. The resulting solution wasstirred for 20 min at 0° C. The above mixture was added to a saturatedsolution of SO₂ in AcOH (20 mL) and CuCl₂ (800 mg, 5.95 mmol) dropwisewith stirring at 0° C. The resulting solution was stirred for 1 h at RT.The reaction was then quenched by the addition of 20 mL of water. Theresulting solution was extracted with 3×20 mL of ethyl acetate and theorganic layers combined and dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. This resulted in 1.5 g (crude) of the titlecompound as a yellow oil. The crude product was used in the next step.

Steps 2-3 used similar procedures for converting compound 2 toIntermediate 2 shown in Scheme 6 to afford Intermediate 4. MS-ESI: 232.1(M−1).

TABLE 4 The Intermediates in the following Table were prepared using thesimilar procedures for converting compound 7 to Intermediate 4 shown inScheme 9. Intermediate # Structure IUPAC Name Mass Spec [M − H]⁻Intermediate 5

3-fluoro-5-(2- hydroxypropan-2- yl)benzenesulfonamide 232.1 Intermediate6

3,5-bis(2-hydroxypropan- 2-yl) benzenesulfonamide 272.1

3-(2-Hydroxypropan-2-yl)-5-(pyridin-4-yl)benzenesulfonamide Step 1:Ethyl 3-nitro-5-(pyridin-4-yl)benzoate

Into a 500-mL round-bottom flask purged with and maintained undernitrogen, was placed ethyl 3-bromo-5-nitrobenzoate (5.5 g, 20.1 mmol),dioxane (250 mL), water (50 mL), (pyridin-4-yl)boronic acid (3.0 g, 24.4mmol), Cs₂CO₃ (12.7 g, 38.98 mmol), and Pd(dppf)Cl₂ (600 mg, 0.82 mmol).The resulting solution was stirred for 12 h at 100° C. and then wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:1 to 3:1). Thisresulted in 4.2 g (77%) of the title compound as a white solid. MS-ESI:273.1 (M+1).

Step 2: Ethyl 3-amino-5-(pyridin-4-yl)benzoate

Into a 250-mL round-bottom flask, was placed ethyl3-nitro-5-(pyridin-4-yl)benzoate (4.2 g, 15.4 mmol) and MeOH (150 mL).Then Pd/C (10% wt, 500 mg) was added. The flask was evacuated andflushed three times with hydrogen. The resulting solution was stirredfor 2 days at RT under an atmosphere of hydrogen. The solids were thenfiltered out. The resulting solution was concentrated under vacuum,resulting in 3.7 g (99%) of the title compound as a white solid. MS-ESI:243.1 (M+1).

Steps 3-5 used the similar procedures for converting compound 7 toIntermediate 4 shown in Scheme 9 to afford Intermediate 7. MS-ESI: 293.1(M+1), 291.1 (M−1).

TABLE 5 The Intermediate in the following Table was prepared using thesimilar procedures for converting compound 10 to Intermediate 7 shown inScheme 10. Intermediate # Structure IUPAC Name Mass Spec [M − H]⁻Intermediate 8

5-(2-hydroxypropan-2- yl)biphenyl-3- sulfonamide 290.1

3 -(2-Hydroxypropan-2-yl)-5-morpholinobenzenesulfonamide Step 1: Ethyl3-bromo-5-nitrobenzoate

Into a 500-mL round-bottom flask, was placed 3-bromo-5-nitrobenzoic acid(25 g, 101.6 mmol), EtOH (200 mL). This was followed by the addition ofSOCl₂ (15 mL) dropwise with stirring at 0° C. The resulting solution wasstirred for 4 h at 80° C. and then was quenched by the addition of 50 mLwater. The resulting solution was extracted with 3×50 mL of DCM and theorganic layers combined and concentrated under vacuum. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:20 to 1:10). This resulted in 27.5 g (99%) of the titlecompound as a white solid.

Step 2: Ethyl 3 -(morpholin-4-yl)-5-nitrobenzoate

Into a 500-mL round-bottom flask purged with and maintained undernitrogen, was placed ethyl 3-bromo-5-nitrobenzoate (10 g, 36.5 mmol),toluene (250 mL), morpholine (4.6 g, 52.8 mmol), t-BuONa (5 g, 52.0mmol), Pd₂(dba)₃CHCl₃ (1.9 g, 1.93 mmol), and BINAP (1.2 g, 1.93 mmol).The resulting solution was stirred for 18 h at 60° C. and then wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:30 to 1:10).This resulted in 2.8 g (27%) of the title compound as a yellow solid.MS-ESI: 281.1 (M+1).

Step 3: Ethyl 3-amino-5-(morpholin-4-yl)benzoate

Into a 250-mL round-bottom flask, was placed ethyl3-(morpholin-4-yl)-5-nitrobenzoate (3.0 g, 10.7 mmol) and MeOH (100 mL).Then Pd/C (10% wt, 300 mg) was added. The flask was evacuated andflushed three times with hydrogen. The resulting solution was stirredfor 12 h at RT under an atmosphere of hydrogen. The solids were filteredout. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:5 to 1:3). This resulted in 2.6 g (97%) ofthe title compound as a yellow solid. MS-ESI: 251.1 (M+1).

Steps 4-6 used the similar procedures for converting compound 7 toIntermediate 4 shown in Scheme 9 to afford Intermediate 9. MS-ESI: 299.1(M−1).

3-(Hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1:1-Oxo-1,3-dihydroisobenzofuran-5-sulfonyl chloride

Into a 100-mL round-bottom flask, was placed5-aminoisobenzofuran-1(3H)-one (1 g, 6.70 mmol), HCl (6 M, 10 mL). Thiswas followed by the addition of a solution of NaNO₂ (603 mg, 8.74 mmol)in water (5 mL) dropwise with stirring at 0° C. The above mixture wasadded to a saturated solution of SO₂ in AcOH (20 mL) dropwise withstirring at 0° C. Then to the above was added CuCl₂ (890 mg, 6.62 mmol).The resulting solution was stirred for 1 h at RT and then was quenchedby the addition of 30 mL of water. The resulting solution was extractedwith 3×30 mL of DCM and the organic layers combined and dried overanhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 1.1 g(crude, 71%) of the title compound as brown oil. The crude product wasused in the next step.

Step 2: 1-Oxo-1,3-dihydroisobenzofuran-5-sulfonamide

Into a 100-mL round-bottom flask, was placed1-oxo-1,3-dihydroisobenzofuran-5-sulfonyl chloride (1.1 g, 4.73 mmol),DCM (20 mL). To the above was added a saturated solution of ammonia inDCM (20 mL). The resulting solution was stirred for 2 h at RT and thenwas concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). Thisresulted in 480 mg (48%) of the title compound as a yellow solid.MS-ESI: 212.0 (M−1).

Step 3: 3 -(Hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 100-mL 3-necked round-bottom flask purged with and maintainedunder nitrogen, was placed a solution of1-oxo-1,3-dihydroisobenzofuran-5-sulfonamide (310 mg, 1.45 mmol) in THF(10 mL). This was followed by the addition MeMgBr/THF (3 M, 4.85 mL)dropwise with stirring at 0° C. The resulting solution was stirredovernight at RT and then was quenched by the addition of 10 mL of NH₄Cl(sat.). The resulting solution was extracted with 5×10 mL of ethylacetate and the organic layers combined and dried over anhydrous Na₂SO₄,then concentrated under vacuum. The crude product was purified byPrep-HPLC using method E eluted with a gradient of 5∞20% ACN. Thisresulted in 200 mg (56%) of the title compound as a white solid. MS-ESI:244.1 (M−1).

TABLE 6 The Intermediate in the following Table was prepared using thesimilar procedures for converting compound 32 to Intermediate 20 shownin Scheme 20. Intermediate # Structure IUPAC Name Mass Spec [M + H]⁺Intermediate 21

6-(2-hydroxypropan-2-yl) pyridine-3-sulfonamide 217.1

TABLE 7 The Intermediate in the following Table was prepared using thesimilar procedures for converting compound 32 to compound 34 shown inScheme 20. Mass Spec Intermediate # Structure IUPAC Name [M − H]⁻Intermediate 22

methyl 4-fluoro-3-sulfamoylbenzoate 232.0

Schemes for amine Intermediates: Schemes 13-21 illustrate the amineintermediates preparation.

4-Fluoro-2,6-diisopropylbenzenamine Step 1:4-Fluoro-2,6-di(prop-1-en-2-yl)benzenamine

Into a 500-mL round-bottom flask purged with and maintained undernitrogen, was placed 2,6-dibromo-4-fluorobenzenamine (15 g, 55.8 mmol),dioxane (150 mL), water (15 mL), Cs₂CO₃ (55 g, 169 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25 g, 149mmol), and Pd(dppf)Cl₂ (4 g, 5.47 mmol). The resulting solution wasstirred for 15 h at 100° C. and then was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:10 to 1:8). This resulted in 9.2 g (86%) ofthe title compound as brown oil. MS-ESI: 192.1 (M+1).

Step 2: 4-Fluoro-2,6-diisopropylbenzenamine

Into a 500-mL round-bottom flask, was placed4-fluoro-2,6-di(prop-1-en-2-yl)benzenamine (9.2 g, 48.1 mmol) and MeOH(200 mL). Then Pd/C (10% wt, 900 mg) was added. The flask was evacuatedand flushed three times with hydrogen. The resulting solution wasstirred for 12 h at RT under an atmosphere of hydrogen. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:10 to 1:8). This resulted in 7.2 g (77%) ofthe title compound as brown oil. MS-ESI: 196.1 (M+1).

3-Fluoro-2,6-diisopropylbenzenamine Step 1:2,6-Dibromo-4-chloro-3-fluorobenzenamine

Into a 500-mL round-bottom flask, was placed4-chloro-3-fluorobenzenamine (5.08 g, 34.9 mmol), ACN (200 mL), and NB S(18.69 g, 105.0 mmol). The resulting solution was stirred for 12 h at RTand then was concentrated under vacuum. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:200to 1:100). This resulted in 9.7 g (92%) of the title compound as a lightyellow solid. MS-ESI: 303.8, 305.8, 301.8 (M+1).

Step 2: 4-Chloro-3-fluoro-2,6-di(prop-1-en-2-yl)benzenamine

Into a 500-mL round-bottom flask purged with and maintained undernitrogen, was placed 2,6-dibromo-4-chloro-3-fluorobenzenamine (9.03 g,29.8 mmol), dioxane (200 mL), water (20 mL),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.12 g,89.98 mmol), Cs₂CO₃ (29.34 g, 90.05 mmol), and Pd(dppf)Cl₂ (2.20 g, 3.01mmol). The resulting solution was stirred for 12 h at 100° C. and thenwas concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:30 to 1:20).This resulted in 4.3 g (64%) of the title compound as yellow oil.MS-ESI: 226.1, 228.1 (M+1).

Step 3: 3-Fluoro-2,6-diisopropylbenzenamine

Into a 250-mL pressure tank reactor (10 atm) purged with and maintainedunder nitrogen, was placed4-chloro-3-fluoro-2,6-di(prop-1-en-2-yl)benzenamine (4.3 g, 19.1 mmol),MeOH (100 mL), and TEA (2.0 g, 19.8 mmol). Then Pd/C (10% wt, 0.5 g) wasadded. The flask was evacuated and flushed three times with hydrogen.The resulting solution was stirred for 7 days at 100° C. under anatmosphere of hydrogen. The solids were filtered out. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:5 to1:3). This resulted in 3.6 g (97%) of the title compound as a lightyellow oil. MS-ESI: 196.1 (M+1).

4-Chloro-2,6-diisopropylbenzenamine Step 1:4-Chloro-2,6-diisopropylbenzenamine

Into a 100-mL round-bottom flask, was placed 2,6-diisopropylbenzenamine(5 g, 28.2 mmol), DMF (20 mL), and NCS (4.9 g, 36.7 mmol). The resultingsolution was stirred for 15 h at RT and then was diluted with 20 mL ofwater. The resulting solution was extracted with 3×20 mL of DCM and theorganic layers combined and concentrated under vacuum. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:10 to 1:5). This resulted in 3.7 g (62%) of the title compoundas brown oil. MS-ESI: 212.1, 214.1 (M+1).

4-Amino-3,5-diisopropylbenzonitrile Step 1:4-Amino-3,5-diisopropylbenzonitrile

Into a 100-mL round-bottom flask purged with and maintained undernitrogen, was placed 4-bromo-2,6-diisopropylbenzenamine (commercialavailable, 5.1 g, 19.9 mmol), DMF (30 mL), CuCN (2.16 g, 23.9 mmol), CuI(380 mg, 2.00 mmol), KI (664 mg, 3.98 mmol), and DMEDA (2.0 mL). Theresulting solution was stirred for 24 h at 100° C. and then was dilutedwith 30 mL of water. The solution was extracted with 3×30 mL of ethylacetate and the organic layers combined and concentrated under vacuum.The residue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:30 to 1:20). This resulted in 1.2 g (30%) ofthe title compound as a yellow solid. MS-ESI: 203.1 (M+1).

4-Amino-3,5-diisopropylbenzamide Step 1:4-Amino-3,5-diisopropylbenzamide

Into a 25-mL round-bottom flask, was placed4-amino-3,5-diisopropylbenzonitrile (141 mg, 0.70 mmol), DMSO (3 mL),K₂CO₃ (70 mg, 0.51 mmol), and H₂O₂ (0.2 mL). The resulting solution wasstirred for 3 h at RT and then was diluted with 5 mL of water. Theresulting solution was extracted with 3×5 mL of ethyl acetate and theorganic layers combined and dried over anhydrous Na₂SO_(4,) thenconcentrated under vacuum. This resulted in 145 mg (94%) of the titlecompound as a yellow solid. MS-ESI: 221.2 (M+1).

Methyl 4-amino-3,5-diisopropylbenzoate Step 1: Methyl4-amino-3,5-diisopropylbenzoate

Into a 100-mL round-bottom flask, was placed4-bromo-2,6-diisopropylbenzenamine (2.161 g, 8.44 mmol), DMF (20 mL),MeOH (20 mL), and Pd(dppf)Cl₂ (1.24 g, 1.69 mmol). The resultingsolution was stirred for 16 h at 120° C. under an atmosphere of CO andthen diluted with 20 mL of water. The resulting solution was extractedwith 3×20 mL of ethyl acetate and the organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:60 to 1:40).This resulted in 341 mg (17%) of the title compound as yellow oil.MS-ESI: 236.2 (M+1).

8-Chloro-1,2,3,5,6,7-hexahydros-indacen-4-amine Step 1:8-Chloro-1,2,3,5,6,7-hexahydros-indacen-4-amine

Into a 100-mL round-bottom flask, was placed1,2,3,5,6,7-hexahydros-indacen-4-amine (1.73 g, 9.99 mmol), DMF (10 mL),and NCS (1.47 g, 11.0 mmol). The resulting solution was stirred for 12 hat RT and then was diluted with 50 mL of DCM. The resulting mixture waswashed with 3×10 mL of water. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1:10 to 1:5). This resultedin 1.88 g (91%) of the title compound as a yellow solid. MS-ESI: 208.1,210.1 (M+1).

8-Fluoro-1,2,3,5,6,7-hexahydros-indacen-4-amine Step 1:8-Nitro-1,2,3,5,6,7-hexahydros-indacen-4-amine

Into a 500-mL round-bottom flask, was placed1,2,3,5,6,7-hexahydros-indacen-4-amine (8 g, 46.17 mmol), EtOH (200 mL),and 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (21.6 g,46.08 mmol). The resulting solution was stirred for 12 h at RT and thenwas concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:50 to 1:30).This resulted in 5 g (50%) of the title compound as a yellow solid.MS-ESI: 219.1 (M+1).

Step 2: 4-Fluoro-8-nitro-1,2,3,5,6,7-hexahydros-indacene

Into a 100-mL round-bottom flask, was placed8-nitro-1,2,3,5,6,7-hexahydros-indacen-4-amine (5 g, 22.91 mmol), HF/Py(70% wt, 20 mL). This was followed by the addition of 3-methylbutylnitrite (3 g, 25.61 mmol) dropwise with stirring at 0° C. The resultingsolution was stirred for 2 h at RT and then was diluted with 50 mL ofwater. The resulting solution was extracted with 3×50 mL of DCM and theorganic layers combined and dried over anhydrous Na₂SO₄, thenconcentrated under vacuum. This resulted in 4 g (crude, 79%) of thetitle compound as brown oil.

Step 3: 8-Fluoro-1,2,3,5,6,7-hexahydros-indacen-4-amine

Into a 100-mL round-bottom flask, was placed4-fluoro-8-nitro-1,2,3,5,6,7-hexahydros-indacene (4 g, 18.08 mmol) andMeOH (50 mL). Then Pd/C (10% wt, 0.5 g) was added. The flask wasevacuated and flushed three times with hydrogen. The resulting solutionwas stirred for 12 h at RT under an atmosphere of hydrogen. The solidswere filtered out and the mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:10 to 1:5). This resulted in 2 g (58%) of thetitle compound as a white solid. MS-ESI: 192.1 (M+1).

8-Amino-1,2,3,5,6,7-hexahydros-indacene-4-carbonitrile Step 1:8-Amino-1,2,3,5,6,7-hexahydros-indacene-4-carbonitrile

Into a 50-mL round-bottom flask purged with and maintained undernitrogen, was placed 8-bromo-1,2,3,5,6,7-hexahydros-indacen-4-amine (725mg, 2.88 mmol), DMF (10 mL), t-BuOK (330 mg, 2.90 mmol), CuCN (386 mg,4.32 mmol), Pd(dppf)Cl₂ (424 mg, 0.58 mmol), and Pd(PPh₃)₄ (334 mg, 0.29mmol). The resulting solution was stirred for 12 h at 120° C. anddiluted with 20 mL of water. The resulting solution was extracted with3×20 mL ethyl acetate and the organic layers combined and dried overanhydrous Na₂SO₄, then concentrated under vacuum. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:60 to 1:40). This resulted in 192 mg (34%) of the titlecompound as a yellow solid. MS-ESI: 199.1 (M+1).

Example 2

3-Chloro-N-(8-chloro-1,2,3,5,6,7-hexahydros-indacen-4-ylcarbamoyl)-5-(2-hydroxypropan-2-yl)benzenesulfonamide (Scheme 2)

Into a 50-mL round-bottom flask purged with and maintained undernitrogen, was placed 8-chloro-1,2,3,5,6,7-hexahydros-indacen-4-amine (72mg, 0.35 mmol), THF (3 mL), TEA (35 mg, 0.35 mmol), BTC (35 mg, 0.12mmol). The resulting solution was stirred for 2 h at 65° C. and then wasconcentrated under vacuum. The above mixture diluted in THF (1 mL) wasadded to a solution of3-chloro-5-(2-hydroxypropan-2-yl)benzenesulfonamide (86 mg, 0.34 mmol)and CH₃ONa (94 mg, 1.74 mmol) in THF (3 mL). The resulting solution wasstirred for 3 h at RT and then was concentrated under vacuum. The crudeproduct was purified by Prep-HPLC using method E eluted with a gradientof 30˜60% ACN. This resulted in 42.0 mg (25%) of the title compound as awhite solid. MS-ESI: 483.1 (M+1). ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.03 (s,1H), 7.85 (s, 1H), 7.73 (s, 1H), 2.86 (t, J=7.6 Hz, 4H), 2.72 (t, J=7.2Hz, 4H), 2.07-1.99 (m, 4H), 1.53 (s, 6H).

Example 3

N-(4-cyano-2,6-diisopropylphenylcarbamoyl)-3-fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide(Scheme 3)

Into a 50-mL round-bottom flask purged with and maintained undernitrogen, was placed 4-amino-3,5-diisopropylbenzonitrile (59 mg, 0.29mmol), THF (3 mL), TEA (30 mg, 0.30 mmol), and BTC (25 mg, 0.08 mmol).The resulting solution was stirred for 2 h at 65° C. and then wasconcentrated under vacuum.

The above mixture diluted in THF (1 mL) was added to a solution of3-fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide (67 mg, 0.29 mmol)and DBU (66 mg, 0.43 mmol) in THF (3 mL). The resulting solution wasstirred for 2 h at RT and then was concentrated under vacuum. The crudeproduct was purified by Prep-HPLC using method E eluted with a gradientof 10˜30% ACN. This resulted in 42.3 mg (32%) of title compound as awhite solid. MS-ESI: 460.3 (M+1). ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.97 (s,1H), 7.63 (d, J=8.0 Hz, 1H), 7.54-7.49 (m, 1H), 7.49 (s, 2H), 3.02-2.95(m, 2H), 1.55 (s, 6H), 1.11 (d, J=4.8 Hz, 12H).

Example 4

N-(1,2,3,5,6,7-hexahydros-indacen-4-ylcarbamoyl)-3,5-bis(2-hydroxypropan-2-yl)benzenesulfonamide(Scheme 4)

Into a 50-mL round-bottom flask purged with and maintained undernitrogen, was placed 1,2,3,5,6,7-hexahydros-indacen-4-amine (64 mg, 0.37mmol), THF (2 mL), TEA (38 mg, 0.38 mmol), and BTC (37 mg, 0.12 mmol).The resulting solution was stirred for 2 h at 65° C. and then wasconcentrated under vacuum. The above mixture diluted in DCM (1 mL) wasadded to a solution of 3,5-bis(2-hydroxypropan-2-yl)benzenesulfonamide(100 mg, 0.37 mmol) and TEA (38 mg, 0.38 mmol) in DCM (3 mL). Theresulting solution was stirred for 3 h at RT and then was concentratedunder vacuum. The crude product was purified by Prep-HPLC using method Eeluted with a gradient of 10˜60% ACN. This resulted in 90 mg (52%) ofthe title compound as a white solid. MS-ESI: 471.2 (M−1). ¹H NMR (400MHz, CD₃OD-d₄) δ 8.01 (s, 2H), 7.91 (s, 1H), 6.91 (s, 1H), 2.81 (t,J=7.2 Hz, 4H), 2.57 (t, J=6.8 Hz, 4H), 2.00-1.92 (m, 4H), 1.55 (s, 12H).

Example 5

N-(1,2,3,5,6,7-hexahydros-indacen-4-ylcarbamoyl)-3-(2-hydroxypropan-2-yl)-5-morpholinobenzenesulfonamide(Scheme 5)

Into a 50-mL round-bottom flask purged with and maintained undernitrogen, was placed 1,2,3,5,6,7-hexahydros-indacen-4-amine (71 mg, 0.41mmol), THF (20 mL), TEA (42 mg, 0.42 mmol), and BTC (37 mg, 0.12 mmol).The resulting solution was stirred for 2 h at 65° C. and then wasconcentrated under vacuum. The above mixture diluted in THF (3 mL) wasadded to a solution of3-(2-hydroxypropan-2-yl)-5-morpholinobenzenesulfonamide (110 mg, 0.37mmol) and TEA (42 mg, 0.42 mmol) in THF (5 mL). The resulting solutionwas stirred for 3 h at RT and then was concentrated under vacuum. Thecrude product was purified by Prep-HPLC using method E eluted with agradient of 10˜60% ACN. This resulted in 88.6 mg (43%) of the titlecompound as a white solid. MS-ESI: 500.2 (M+1). ¹H NMR (400 MHz,CD₃OD-d₄) δ 7.57 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 6.92 (s, 1H), 3.83(t, J=4.8 Hz, 4H), 3.21 (t, J=4.8 Hz, 4H), 2.82 (t, J=7.2 Hz, 4H), 2.69(t, J=7.2 Hz, 4H), 2.07-1.94 (m, 4H), 1.53 (s, 6H).

TABLE 8 Examples in the following table were prepared using similarconditions as described in Example 2 and Scheme 2 from appropriatestarting materials. Mass Example Spec # Compound Structure IUPAC Name [M− H]⁻ 6 120

3-chloro-N-(2,6- diisopropylphenyl carbamoyl)-5-(2- hydroxypropan-2-yl)benzenesulfona- mide 435.1 (M − OH)⁺ 7 101

3-chloro-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5- (2-hydroxypropan-2- yl)benzenesulfona- mide 447.2 8 124

4-(3-(3-chloro-5- (2- hydroxypropan-2- yl)phenylsulfonyl) ureido)-3,5-diisopropylbenza- mide 496.2 (M + 1) 9 114

3-fluoro-N-(8- fluoro-1,2,3,5,6,7- hexahydros- indacen-4-ylcarbamoyl)-5- (2- hydroxypropan-2- yl)benzenesulfona- mide 449.1 10125

N-(2,6- diisopropylphenyl carbamoyl)-3- fluoro-5-(2- hydroxypropan-2-yl)benzenesulfona- mide 437.2 (M + 1) 11 102

3-fluoro-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5- (2-hydroxypropan-2- yl)benzenesulfona- mide 431.1 12 147

N-(4-cyano-2,6- diisopropylphenyl carbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfona- mide 442.1

TABLE 9 Examples in the following table were prepared using similarconditions as described in Example 3 and Scheme 3 from appropriatestarting materials. Mass Example Spec # Compound Structure IUPAC Name [M− H]⁻ 13 144

3-fluoro-N-(3- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 453.1 14 150

N-(4-chloro-2,6- diisopropylphenyl- carbamoyl)-3- fluoro-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 469.2 15 109

N-(8-cyano- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3-fluoro-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 456.1 16 127

3-fluoro-N-(4- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 453.2 17 131

2-fluoro-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 415.1 (M − OH)⁺ 18 137

3-chloro-N-(3- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 469.2 19 138

3-chloro-N-(4- cyano-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 476.2 20 123

3-chloro-N-(4- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 469.2 21 113

3-chloro-N-(8- fluoro-1,2,3,5,6,7- hexahydros- indacen-4-ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 467.1(M + 1) 22 108

3-chloro-N-(8- cyano-1,2,3,5,6,7- hexahydros- indacen-4-ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 472.1 23 154

3-chloro-N-(4- chloro-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 485.1 24 112

3-cyano-N-(8- fluoro-1,2,3,5,6,7- hexahydros- indacen-4-ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 456.1 25 106

3-cyano-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 438.1 26 110

N-(8-chloro- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3-cyano-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 474.2 (M + 1) 27117

3-cyano-N-(4- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 460.3 28 116

3-cyano-N-(4- cyano-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 467.2 29 145

N-(4-chloro-2,6- diisopropylphenyl- carbamoyl)-3- cyano-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 476.1 30 148

3-cyano-N-(3- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfona- mide 460.1 31 115

3-cyano-N-(2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2-yl)benzenesulfona- mide 442.1 32 107

3-cyano-N-(8- cyano-1,2,3,5,6,7- hexahydros- indacen-4-ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 463.1 33 141

N-(3-fluoro-2,6- diisopropylphenyl- carbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfona- mide 435.2 34 111

N-(8-fluoro- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3-(2-hydroxypropan-2- yl)benzenesulfona- mide 431.2 35 105

N-(8-cyano- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3-(2-hydroxypropan-2- yl)benzenesulfona- mide 438.2 36 158

methyl 4-(3-(3-(2- hydroxypropan-2- yl)phenylsulfonyl) ureido)-3,5-diisopropylbenzoate 475.2 37 167

N-(1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2- yl)benzenesulfona- mide 415.2 (M + 1) 38 166

N-(1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-6-(2-hydroxypropan-2- yl)pyridine-3- sulfonamide 414.1 39 171

methyl 3-(N-(4- chloro-2,6- diisopropylphenyl- carbamoyl) sulfamoyl)-4-fluorobenzoate 471.1 (M + 1)

TABLE 10 Examples in the following table were prepared using similarconditions as described in Example 4 and Scheme 4 from appropriatestarting materials. Mass Example Spec # Compound Structure IUPAC Name [M− H]⁻ 40 155

N-(3-fluoro-2,6- diisopropylphenyl- carbamoyl)-3,5- bis(2-hydroxypropan-2- yl)benzene- sulfonamide 493.3 41 149

N-(1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-3- (2-hydroxy-propan-2-yl)-5- (pyridin-4-yl) benzene- sulfonamide 492.2 (M + 1) 42 159

N-(3-fluoro-2,6- diisopropyl- phenylcarbamoyl)- 3-(2-hydroxy-propan-2-yl)-5- (pyridin-4-yl) benzene- sulfonamide 514.2 (M + 1) 43 151

N-(1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-5- (2-hydroxy-propan-2-yl) biphenyl-3- sulfonamide 473.2 (M − OH)⁺ 44 153

N-(3-fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2-yl)biphenyl-3- sulfonamide 495.3 (M − OH)⁺ 45 160

N-(8-fluoro- 1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-4-(2-hydroxy- propan-2-yl) benzene- sulfonamide 433.1 46 161

N-(8-chloro- 1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-4-(2-hydroxy- propan-2-yl) benzene- sulfonamide 449.1 47 164

N-(8-cyano- 1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-4-(2-hydroxy- propan-2-yl) benzene- sulfonamide 440.1 48 162

N-(4-chloro- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy-propan-2-yl) benzene- sulfonamide 453.2 49 165

N-(4-fluoro- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy-propan-2-yl) benzene- sulfonamide 437.2 50 168

N-(4-cyano- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy-propan-2-yl) benzene- sulfonamide 444.1 51 169

N-(2,6- diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy- propan-2-yl)benzene- sulfonamide 419.1 52 170

N-(3-fluoro- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy-propan-2-yl) benzene- sulfonamide 437.3

TABLE 11 The example in the following table was prepared using similarconditions as described in Example 5 and Scheme 5 from appropriatestarting materials. Mass Example Spec # Compound Structure IUPAC Name[M + H]⁺ 53 157

N-(3-fluoro- 2,6-diisopropyl- phenyl- carbamoyl)-3- (2-hydroxy-propan-2-yl)- 5-morpholino- benzene- sulfonamide 522.3 54 163

N-(1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)- 3-(hydroxy-methyl)-4-(2- hydroxy- propan-2-yl) benzene- sulfonamide 443.2

Bioassay:

IL-1β Production in PMA-Differentiated THP-1 Cells Stimulated WithGramicidin.

Procedure 1:

Cell culture-THP-1 cells were purchased from the American Type CultureCollection and sub-cultured according to instructions from the supplier.Prior to experiments, cells were cultured in RPMI 1640 containing 10%heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100μg/ml), and maintained in log phase prior to experimental setup. Priorto the experiment THP-1 were treated with PMA (Phorbol 12-myristate13-acetate) (10 μg/ml) for 24 hours. The day of the experiment the mediawas removed and attaching cells were treated with trypsin for 2 minutes,cells were then collected, washed with PBS (phosphate buffer saline),spin down, resuspended in 2% heat inactivated FBS with RPMI at aconcentration of 1×106 cells/ml, and 100 μl was plated in a 96 wellplate. Cells were incubated with compounds for 1 hours and thenstimulated with Gramicidin (5 μM) (Enzo) for 2 hours. Cell freesupernatant was collected and the production of IL-1β was evaluated byELISA. Compounds were dissolved in dimethyl sulfoxide (DMSO) and addedto the culture medium to achieve desired concentration (e.g. 100, 30,10, 3, 1, 0.3 or 0.1 μM). A vehicle only control was run concurrentlywith each experiment. Final DMSO concentration was 1%. Compounds exhibita dose-related inhibition of IL-1β production in PMA-differentiatedTHP-1 cells.

Procedure 2:

THP-1 cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Prior toexperiments, cells were cultured in complete RPMI 1640 (containing 10%heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100μg/ml)), and maintained in log phase prior to experimental setup. Priorto the experiment THP-1 were treated with PMA (Phorbol 12-myristate13-acetate) (20 ng/ml) for 16-18 hours. On the day of the experiment themedia was removed and adherent cells were detached with trypsin for 5minutes. Cells were then harvested, washed with complete RPMI 1640, spundown, resuspended in RPMI 1640 (containing 2% heat inactivated FBS,penicillin (100 units/ml) and streptomycin (100 μg/ml). The cells wereplated in a 384-well plate at a density of 50,000 cells/well (finalassay volume 50 μl). Compounds were dissolved in dimethyl sulfoxide(DMSO) and added to the culture medium to achieve desired concentration(e.g. 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017μM). Cells were incubated with compounds for 1 hour and then stimulatedwith gramicidin (5 μM) (Enzo) for 2 hours. Cell free supernatant wascollected and the production of IL-1β was evaluated by HTRF (cisbio). Avehicle only control was run concurrently with each experiment. FinalDMSO concentration was 0.38%. Compounds exhibited aconcentration-dependent inhibition of IL-1β production inPMA-differentiated THP-1 cells.

IC₅₀ values (μm) of compounds of the formulae herein tested inaccordance with the protocol above gave IC₅₀ values of less than about30 μm.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

We claim:
 1. A compound of Formula II

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is NH or O; or when X¹ is NH, X¹ and R² taken together with the atomsconnecting them form a four-to-seven-membered heterocyclic ringoptionally substituted with one or more R¹⁶; or when X¹ is NH, X¹ and R⁴taken together with the atoms connecting them form afour-to-seven-membered heterocyclic ring optionally substituted with oneor more R¹⁶; Y is N or CR⁸; Y′ is N or CR^(8′); Z is N or CH; R⁸ isselected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,CONR¹¹R¹², C₁-C₆ alkyl, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl; R^(8′) isselected from H, CN, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹²,C₁-C₆ alkyl, and C₁-C₆ haloalkyl; R^(8″) is selected from CN, Cl, F,CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆haloalkyl; R^(8′″) is selected from H, CN, CO₂C₁-C₆ alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; R² is hydrogen,C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl optionallysubstituted with hydroxy; R³ is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆ alkyl optionally substituted with hydroxy; R^(3′) ishydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyloptionally substituted with hydroxy; R⁴ is hydrogen, C₁-C₆ alkoxy, halo,C₁-C₆ haloalkyl, or C₁-C₆ alkyl optionally substituted with hydroxy; R⁵is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyloptionally substituted with hydroxy; R^(5′) is hydrogen, CN, C₁-C₆alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl optionally substitutedwith hydroxy; provided that at least one of R², R³, R⁴ and R⁵ is nothydrogen, and that R² and R⁴ are not both hydroxymethyl; or R² and R³,if both present, taken together with the carbons connecting them form afour-membered to seven-membered ring A, or R⁴ and R⁵, if both present,taken together with the carbons connecting them form a four-membered toseven-membered ring B, or R² and R³, if both present, taken togetherwith the carbons connecting them form a four-membered to seven-memberedring A and R⁴ and R⁵, if both present, taken together with the carbonsconnecting them form a four-membered to seven-membered ring B, R^(2′)and R^(3′), if both present, taken together with the carbons connectingthem form a four-membered to seven-membered ring A and R^(4′) andR^(5′), if both present, taken together with the carbons connecting themform a four-membered to seven-membered ring B, wherein ring A is

and ring B is

wherein ring A is a carbocyclic ring or a heterocyclic ring containing 1or 2 heteroatoms independently selected from O, N, and S; n1 is from 2to 5; m1 is from 1 to 10; wherein ring B is a carbocyclic ring or aheterocyclic ring containing 1 or 2 heteroatoms independently selectedfrom O, N, and S; n2 is from 2 to 5; m2 is from 1 to 10; wherein each R⁶in each ring is the same or different and is selected from H, C₁-C₆alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; or two R⁶ taken togetherwith the atom or atoms connecting them form a 3-to-8-memberedcarbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatomsindependently selected from O, N, and S; R¹ is selected from CN, Cl,C(R¹⁰)₂OH, or F; R^(1′) is selected from C(O)C₁-C₆ alkyl or CO₂C₁-C₆alkyl; R^(1″) is selected from H or C(R¹⁰)₂OH; R¹⁴ is selected from H,CN, Cl, or F; R^(14′) is selected from CN or F; R^(14″) is selected fromCN, Cl, or F; R⁹ is selected from H, C₁-C₆ alkyl, C(R¹⁰)₂OH,C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl; wherein,when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆ heterocycloalkyl, R⁹is optionally substituted with one or more substituents eachindependently selected from ═NR¹³, COOC₁-C₆ alkyl, and CONR¹¹R¹²; R^(9′)is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆cycloalkyl, phenyl, pyridyl, and morpholinyl;each R¹⁰ is the same and isH or C₁-C₆ alkyl; or two R¹⁰ taken together with the carbon connectingthem form a three-to-eight-membered heterocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S, or athree-membered, six-membered, seven-membered, or eight-memberedcarbocyclic ring, wherein the heterocyclic ring or carbocyclic ring isoptionally substituted with one or more substituents each independentlyselected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; R¹³is C₁-C₆ alkyl; each of R¹¹ and R¹² at each occurrence is independentlyselected from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸; R¹⁵ is C₁-C₆alkyl; each of R¹⁷ and R¹⁸ at each occurrence is independently selectedfrom hydrogen and C₁-C₆ alkyl; each R¹⁶ is the same or different and isselected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³. 2.A compound of Formula II

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is NH; Y is CR⁸; Y′ is CR^(8′); Z is N or CH; R⁸ is selected from H,CN, Cl, F, and CONR¹¹R¹²; R^(8′) is H; R^(8″) is selected from CN or F;R^(8′″) is selected from H, CN, CO₂C₁-C₆ alkyl, or CONR¹¹R¹²; R² isC₁-C₆ alkyl; R³ is hydrogen or halo; R^(3′) is hydrogen or halo; R⁴ isC₁-C₆ alkyl; R⁵ is hydrogen; R^(5′) is hydrogen; provided that at leastone of R², R³, R⁴ and R⁵ is not hydrogen, and that R² and R⁴ are notboth hydroxymethyl; or R² and R³, if both present, taken together withthe carbons connecting them form a four-membered to seven-membered ringA, or R⁴ and R⁵, if both present, taken together with the carbonsconnecting them form a four-membered to seven-membered ring B, or R² andR³, if both present, taken together with the carbons connecting themform a four-membered to seven-membered ring A and R⁴ and R⁵, if bothpresent, taken together with the carbons connecting them form afour-membered to seven-membered ring B, R^(2″) and R^(3″), if bothpresent, taken together with the carbons connecting them form afour-membered to seven-membered ring A and R^(4″) and R^(5″), if bothpresent, taken together with the carbons connecting them form afour-membered to seven-membered ring B, wherein ring A is

and ring B is

wherein ring A is a carbocyclic ring; n1 is 3; m1 is 1; wherein ring Bis a carbocyclic ring; n2 is 3; m2 is 1; wherein each R⁶ in each ring isthe same or different and is selected from H; R¹ is selected from CN,Cl, C(R¹⁰)₂OH, or F; R^(1″) is selected from H or C(R¹⁰)₂OH; R¹⁴ isselected from H or F; R^(14″) _(is F;) R^(9′) is selected fromC(R¹⁰)₂OH, C₃-C₆ cycloalkyl, phenyl, pyridyl, or morpholinyl each R¹⁰ isthe same and is C₁-C₆ alkyl; each of R¹¹ and R¹² at each occurrence isindependently selected from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸;R¹⁵ is C₁-C₆ alkyl; each of R¹⁷ and R¹⁸ at each occurrence isindependently selected from hydrogen and C₁-C₆ alkyl.
 3. The compound ofany one of claim 1 or 2, wherein Formula II is


4. The compound of any one of claims 1-3, wherein R¹ is C(R¹⁰)₂OH. 5.The compound of any one of claims 1-3, wherein R¹ is CN.
 6. The compoundof any one of claims 1-3, wherein R¹ is Cl.
 7. The compound of any oneof claims 1-3, wherein R¹ is F.
 8. The compound of any one of claims1-7, wherein R^(9′) is pyridyl.
 9. The compound of any one of claims1-7, wherein R^(9′) is morpholinyl.
 10. The compound of any one ofclaims 1-7, wherein R^(9′) is C₃-C₆ cycloalkyl.
 11. The compound of anyone of claim 1 or 2, wherein Formula II is


12. The compound of any one of claim 1, 2, or 11, wherein Z is N. 13.The compound of any one of claim 1, 2, or 11, wherein Z is CH.
 14. Thecompound of any one of claim 1, 2, or 11-13, wherein R^(1″) is H. 15.The compound of any one of claim 1 or 2, wherein Formula II is


16. The compound of any one of claim 1, 2, or 15, wherein R^(14″) is F.17. The compound of any one of claim 1 or 2, wherein Formula II is


18. The compound of any one of claim 1, 2, or 17, wherein


19. The compound of any one of claim 1, 2, 17, or 18, wherein: R^(2″)and R^(3″), taken together with the carbons connecting them form a fivemembered ring A and R^(4″) and R^(5″), taken together with the carbonsconnecting them form a five-membered ring B; ring A is a saturatedcarbocyclic ring; ring B is a saturated carbocyclic ring; n1 is 3; n2 is3; R⁶ is H.
 20. The compound of any one of claim 1, 2, or 17-19, whereinR^(8″) is F.
 21. The compound of any one of claim 1, 2, or 17, wherein


22. The compound of any one of claim 1, 2, 17, or 21, wherein R^(3′) isH or F, and R^(5′) is H.
 23. The compound of any one of claim 1, 2, 17,21, or 22, wherein R^(8′″) is H.
 24. The compound of any one of claim 1,2, 17, 21, or 22, wherein R^(8′″) is CN.
 25. The compound of any one ofclaim 1, 2, 17, 21, or 22, wherein R^(8′″) is CONH₂.
 26. The compound ofany one of claim 1, 2, 17, 21, or 22, wherein R^(8′″) is COCH₃
 27. Thecompound of claim 1, wherein Formula II is


28. The compound of any one of claim 1 or 27, wherein R^(1′) is acetyl.29. The compound of any one of claim 1, 27, or 28, wherein R^(14′) is F.30. The compound of any one of claim 1 or 27-29, wherein R⁹ is H. 31.The compound of any one of claims 1-30, wherein X¹ is NH.
 32. Thecompound of any one of claim 1-17 or 21-31, wherein R² and R⁴ are eachisopropyl.
 33. The compound of any one of claim 1-16 or 27-32, whereinR³ and R⁵ are each H.
 34. The compound of any one of claim 1-16 or27-31, wherein: R² and R³, taken together with the carbons connectingthem form a five membered ring A and R⁴ and R⁵, taken together with thecarbons connecting them form a five-membered ring B; ring A is asaturated carbocyclic ring; ring B is a saturated carbocyclic ring; n1is 3; n2 is 3; R⁶ is H.
 35. The compound of any one of claim 1-14, or27-34, wherein Y is CR⁸.
 36. The compound of claim 35, wherein R⁸ is H.37. The compound of claim 35, wherein R⁸ is CN.
 38. The compound ofclaim 35, wherein R⁸ is Cl.
 39. The compound of claim 35, wherein R⁸ isF.
 40. The compound of claim 35, wherein R⁸ is CO₂NH_(2.)
 41. Thecompound of claim 35, wherein R⁸ is CO₂CH_(3.)
 42. A compound selectedfrom the group consisting of compounds in the Table below: Com- poundStructure 101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

131

132

135

136

and pharmaceutically acceptable sAPPalts thereof.
 43. A compoundselected from the group consisting of compounds in the Table below: Com-pound Structure 137

138

141

142

143

144

145

146

147

148

149

150

151

153

154

155

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

and pharmaceutically acceptable salts thereof.
 44. A pharmaceuticalcomposition comprising a compound or salt as claimed in any one ofclaims 1-43 and one or more pharmaceutically acceptable excipients. 45.A method for modulating NRLP3 activity, the method comprising contactingNRLP3 with a compound as claimed in any one of claims 1-43 or apharmaceutical composition as claimed in claim
 44. 46. The method ofclaim 45, wherein the modulating comprises antagonizing NRLP3.
 47. Themethod of any one of claims 45 to 46, which is carried out in vitro. 48.The method of claims 45 to 47, wherein the method comprises contacting asample comprising one or more cells comprising NRLP3 with the compound.49. The method of any one of claim 45, 46 or 48, which is carried out invivo.
 50. The method of claim 49, wherein the method comprisesadministering the compound to a subject having a disease in which NLRP3signaling contributes to the pathology and/or symptoms and/orprogression of the disease.
 51. The method of claim 50, wherein thesubject is a human.
 52. A method of treating a disease, disorder orcondition that is a metabolic disorder, comprising administering to asubject in need of such treatment an effective amount of a compound asclaimed in any one of claims 1-43 or a pharmaceutical composition asclaimed in claim
 44. 53. The method of claim 52, wherein the metabolicdisorder is Type 2 diabetes, atherosclerosis, obesity or gout.
 54. Amethod of treating a disease, disorder or condition that is a disease ofthe central nervous system, comprising administering to a subject inneed of such treatment an effective amount of a compound as claimed inany one of claims 1-43 or a pharmaceutical composition as claimed inclaim
 44. 55. The method of claim 45, wherein the disease of the centralnervous system is Alzheimer's disease, multiple sclerosis, AmyotrophicLateral Sclerosis or Parkinson's disease.
 56. A method of treating adisease, disorder or condition that is lung disease, comprisingadministering to a subject in need of such treatment an effective amountof a compound as claimed in any one of claims 1-43 or a pharmaceuticalcomposition as claimed in claim
 44. 57. The method of claim 56, whereinthe lung disease is asthma, COPD or pulmonary idiopathic fibrosis.
 58. Amethod of treating a disease, disorder or condition that is liverdisease, comprising administering to a subject in need of such treatmentan effective amount of a compound as claimed in any one of claims 1-43or a pharmaceutical composition as claimed in claim
 44. 59. The methodof claim 58, wherein the liver disease is NASH syndrome, viral hepatitisor cirrhosis.
 60. A method of treating a disease, disorder or conditionthat is pancreatic disease, comprising administering to a subject inneed of such treatment an effective amount of a compound as claimed inany one of claims 1-43 or a pharmaceutical composition as claimed inclaim
 44. 61. The method of claim 60, wherein the pancreatic disease isacute pancreatitis or chronic pancreatitis.
 62. A method of treating adisease, disorder or condition that is kidney disease, comprisingadministering to a subject in need of such treatment an effective amountof a compound as claimed in any one of claims 1-43 or a pharmaceuticalcomposition as claimed in claim
 44. 63. The method of claim 62, whereinthe kidney disease is acute kidney injury or chronic kidney injury. 64.A method of treating a disease, disorder or condition that is intestinaldisease, comprising administering to a subject in need of such treatmentan effective amount of a compound as claimed in any one of claims 1-43or a pharmaceutical composition as claimed in claim
 44. 65. The methodof claim 64, wherein the intestinal disease is Crohn's disease orUlcerative Colitis.
 66. A method of treating a disease, disorder orcondition that is skin disease, comprising administering to a subject inneed of such treatment an effective amount of a compound as claimed inany one of claims 1-43 or a pharmaceutical composition as claimed inclaim
 44. 67. The method of claim 66, wherein the skin disease ispsoriasis.
 68. A method of treating a disease, disorder or conditionthat is musculoskeletal disease, comprising administering to a subjectin need of such treatment an effective amount of a compound as claimedin any one of claims 1-43 or a pharmaceutical composition as claimed inclaim
 44. 69. The method of claim 68, wherein the musculoskeletaldisease is scleroderma.
 70. A method of treating a disease, disorder orcondition that is a vessel disorder, comprising administering to asubject in need of such treatment an effective amount of a compound asclaimed in any one of claims 1-43 or a pharmaceutical composition asclaimed in claim
 44. 71. The method of claim 70, wherein the vesseldisorder is giant cell arteritis.
 72. A method of treating a disease,disorder or condition that is a disorder of the bones, comprisingadministering to a subject in need of such treatment an effective amountof a compound as claimed in any one of claims 1-43 or a pharmaceuticalcomposition as claimed in claim
 44. 73. The method of claim 72, whereinthe disorder of the bones is osteoarthritis, osteoporosis orosteopetrosis disorders.
 74. A method of treating a disease, disorder orcondition that is eye disease, comprising administering to a subject inneed of such treatment an effective amount of a compound as claimed inany one of claims 1-43 or a pharmaceutical composition as claimed inclaim
 44. 75. The method of claim 74, wherein the eye disease isglaucoma or macular degeneration.
 76. A method of treating a disease,disorder or condition that is a disease caused by viral infection,comprising administering to a subject in need of such treatment aneffective amount of a compound as claimed in any one of claims 1-43 or apharmaceutical composition as claimed in claim
 44. 77. The method ofclaim 76, wherein the diseases caused by viral infection is HIV or AIDS.78. A method of treating a disease, disorder or condition that is anautoimmune disease, comprising administering to a subject in need ofsuch treatment an effective amount of a compound as claimed in any oneof claims 1-43 or a pharmaceutical composition as claimed in claim 44.79. The method of claim 78, wherein the autoimmune disease is RheumatoidArthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis,Addison's disease, or pernicious anemia.
 80. The method of claim 79,wherein the autoimmune disease is cancer or aging.
 81. A method oftreating a disease, disorder or condition that is a cancer selectedfrom: acute myeloid leukemia (AML) or chronic myeloid leukemia (CIVIL),myelodysplastic syndromes (MDS); non-small cell lung cancer, such asnon-small cell lung cancer in patients carrying mutation oroverexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALLin patients resistant to glucocorticoids treatment; Langerhan's cellhistiocytosis (LCH); multiple myeloma; promyelocytic leukemia; gastriccancer; and lung cancer metastasis, comprising administering to asubject in need of such treatment an effective amount of a compound asclaimed in any one of claims 1-64 or a pharmaceutical composition asclaimed in claim
 65. 82. The method of claim 81, wherein the cancer isMDS.
 83. The method of claim 81, wherein the cancer is non-small lungcancer.
 84. The method of claim 81, wherein the cancer is acutelymphoblastic leukemia.
 85. The method of claim 81, wherein the canceris LCH.
 86. The method of claim 81, wherein the cancer is multiplemyeloma.
 87. The method of claim 81, wherein the cancer is promyelocyticleukemia.
 88. The method of claim 81, wherein the cancer is gastriccancer.
 89. The method of claim 81, wherein the cancer is lung cancermetastasis.